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      January 14, 2021

      United States Securities and Exchange Commission

      Division of Corporate Finance

      Office of Life Sciences

      Attention: Li Xiao

      100 F Street, NE

      Washington, D.C. 20549

            Re:

              Ionis Pharmaceuticals, Inc.

      Form 10-K for the Fiscal Year Ended December 31, 2019

      Filed March 2, 2020

      File No. 000-19125

      Dear Ms. Xiao:

      On behalf of Ionis Pharmaceuticals, Inc. (the “Company,” “Ionis” or “we”), enclosed for electronic filing via EDGAR pursuant to the Securities Act of 1933, please find responses to your comments in reference to the
        Company’s Form 10-K for the fiscal year ended December 31, 2019, File No. 000-19125.

      As requested by the Staff in your letter, please find below our responses to your comments and our proposed disclosure to be included in future periodic reports.

      Notes to Consolidated Financial Statements

      1. Organization and Significant Accounting Policies

      Inventory Valuation, page F-19

      1. Your disclosure states that inventory is reflected at the lower of cost or market value under the first-in, first-out method. Please revise your future filings to clarify, if true, that your inventory is measured
        at the lower of cost or net realizable value consistent with ASC 330-10-35-1B.

      We respectfully acknowledge the Staff’s comment and confirm that we measure our inventory at the lower of cost or net realizable value consistent with ASC 330-10-35-1B. We will revise our disclosure in future periodic reports beginning with our
        2020 Form 10-K to clarify that our inventory is measured at the lower of cost or net realizable value under the first-in, first-out method.

      2. Long-Term Obligations and Commitments

      Convertible Notes and Call Spread, page F-26

      2. We note your disclosure concerning the call spread transaction that was entered into in conjunction with the December 2019 note exchange. You indicate that the amounts paid/received for
        the note hedges/warrants was recorded in additional paid-in capital. Please tell us how you determined the appropriate accounting treatment for this transaction, including your consideration of whether these financial instruments meet the
        definition of a derivative. Please also revise your accounting policy disclosure accordingly in future filings.

        1

      We structured our response to this question using the following outline:

            I.

              Transaction Background

            II.

              Accounting Analysis

            A.

              Evaluation of Freestanding Financial Instruments and Units of Accounting

            i.

              Freestanding Financial Instruments

            ii.

              Units of Accounting

            B.

              Whether the note hedges and the warrants are liabilities under ASC 480

            C.

              Whether the note hedges and the warrants meet the conditions to be classified in equity

            i.

              Note Hedges

            1.

              Evaluation of Derivative Definition

            2.

              Evaluation of Derivative Scope Exception

            3.

              Accounting Treatment Conclusion

            ii.

              Warrants

            1.

              Evaluation of Derivative Definition

            2.

              Evaluation of Derivative Scope Exception

            3.

              Accounting Treatment Conclusion

            III.

              Accounting Policy Disclosure

            I.

              Transaction Background

      In December 2019, we exchanged $375.6 million of our existing 1% Notes for $439.3 million of new 0.125% Notes. In addition, we issued $109.5 million of the 0.125% Notes to new investors. Together, we will refer to
        these transactions as the “Exchange Transaction.” We completed the Exchange Transaction to refinance a large portion of our existing 1% Notes with new convertible notes that had a lower interest rate, an extended maturity date and a higher
        conversion price.

      In conjunction with the execution of the Exchange Transaction, we executed a call spread transaction, which was comprised of purchasing note hedges and selling warrants. We entered into the call spread to minimize the
        impact of potential economic dilution upon conversion of our 0.125% Notes by increasing the effective conversion price even further.

            II.

              Accounting Analysis

            A.

              Evaluation of Freestanding Financial Instruments and Units of Accounting

            i.

              Freestanding Financial Instruments

      We began our accounting analysis by first evaluating if the 0.125% Notes, note hedges and warrants are considered freestanding financial instruments using the guidance in ASC 480-10.

      ASC 480-10 Freestanding Financial Instrument

      A financial instrument that meets either of the following conditions:

            •

              It is entered into separately and apart from any of the entity’s other financial instruments or equity transactions.

        2

            •

              It is entered into in conjunction with some other transaction and is legally detachable and separately exercisable.

            ➢

              Since the 0.125% Notes, note hedges and warrants are documented under separate contractual arrangements, which can be transferred independently of each other and are separately exercisable and legally detachable, we concluded each
                instrument should be treated as a freestanding financial instrument.

            ii.

              Units of Accounting

      Since the 0.125% Notes, note hedges and warrants (each of these is a “transaction” for purposes of this section) are separate freestanding financial instruments, we evaluated the appropriate units of accounting using
        the guidance in ASC 815-10-15-9.

      The following indicators should be considered in the aggregate and, if present, cause separate transactions to be accounted for as one unit:

            •

              The transactions were entered into contemporaneously and in contemplation of each other

            ➢

              We executed the 0.125% Notes, note hedges and warrants contemporaneously and in contemplation of each other.

            •

              The transactions were executed with the same counterparty (or structured through an intermediary)

            ➢

              The numerous institutional investors who are the holders of 0.125% Notes are not the counterparties of the note hedges and warrants.

            ➢

              The note hedges and warrants have the same counterparties (i.e., three financial institutions).

            •

              The transactions relate to the same risk

            ➢

              The 0.125% Notes and the warrants do not relate to the same risk. The 0.125% Notes contain both interest rate and equity risks while the warrants have only equity risk.

            ➢

              The value of the note hedges fluctuates based on option pricing inputs.

            •

              There is no apparent economic need, nor substantive business purpose, for structuring the transactions separately that could not also have been accomplished in a single transaction

            ➢

              We had a substantive business reason to execute the 0.125% Notes, note hedges and warrants separately:

            o

              We issued the 0.125% Notes to refinance our existing convertible notes with new convertible notes that had a lower interest rate and an extended maturity date.

            o

              Without the issuance of the 0.125% Notes, we wouldn’t have entered into the note hedges and warrants. However, there were substantive business reasons to structure the note hedges and warrants separately from the 0.125% Notes and from
                each other:

        3

            ■

              We issued the note hedges to synthetically raise the conversion price of the 0.125% Notes.

            ■

              We integrated the premiums we paid for the warrants with the proceeds we received from the 0.125% Notes for tax purposes and used the premium we received from the warrants to finance the purchase of the note hedges.

      Since each of the instruments relate to different risks, had unique business purposes and different counterparties, we concluded that each of the instruments should be accounted for separately.

            B.

              Whether the note hedges and warrants are liabilities under ASC 480

      The next part of our accounting analysis was to determine whether the note hedges and/or warrants are liabilities. We evaluated the note hedges and warrants using the guidance in ASC 480-10, which requires that an
        issuer classify a freestanding financial instrument that is within its scope as a liability (or an asset).

      The following instruments are classified as liabilities pursuant to ASC 480-10:

                •
                ASC 480-10-25-4
                A mandatorily redeemable financial instrument, issued in the form of shares, embodied by an unconditional obligation requiring the issuer to redeem the instrument by
                  transferring its assets at a specified or determinable date (or dates) or upon an event certain to occur shall be classified as a liability unless the redemption is required to occur only upon the liquidation or termination of the
                  reporting entity.

            ➢

              ASC 480-10-25-4 is not applicable because the note hedges and warrants are not in the form of outstanding shares.

                •
                ASC 480-10-25-8
                Any financial instrument, other than an outstanding share, that, at inception, has both of the following characteristics:

            •

              It embodies an obligation to repurchase the issuer’s equity shares or is indexed to such an obligation.

            •

              It requires or may require the issuer to settle the obligation by transferring assets.

            ➢

              The criteria for ASC 480-10-25-8 are not applicable because:

            o

              The warrants do not embody an obligation of Ionis to repurchase its shares by transferring assets pursuant to ASC 480-10-25-8 because:

            ■

              The counterparties to the warrants cannot put the warrants back to Ionis.

            ■

              The underlying shares that Ionis would be required to issue under the warrants are not redeemable.

            o

              These criteria are not applicable for the note hedges because the note hedges represent a right for Ionis to receive cash or shares, not an obligation to issue or repurchase shares.

        4

                •
                ASC 480-10-25-14
                A financial instrument that embodies an unconditional obligation outside of the Company’s control, or a financial instrument other than an outstanding share that embodies a
                  conditional obligation, that the issuer must or may settle by issuing a variable number of its equity shares shall be classified as a liability (or an asset in some circumstances) if, at inception, the monetary value of the obligation is
                  based solely or predominantly on any one of the following:

            •

              A fixed monetary amount known at inception (for example, a payable settleable with a variable number of the issuer’s equity shares)

            •

              Variations in something other than the fair value of the issuer’s equity shares (for example, a financial instrument indexed to the Standard and Poor's S&P 500 Index and settleable with a variable number of
                the issuer’s equity shares)

            •

              Variations inversely related to changes in the fair value of the issuer’s equity shares.

            ➢

              The criteria for ASC 480-10-25-14 are not applicable because:

            o

              Although Ionis is contingently obligated to issue a variable number of shares to net settle the warrants, Ionis’ obligation is:

            ■

              Not predominately fixed;

            ■

              Directly related to the value of Ionis’ stock price (i.e., as Ionis’ stock price increases, the monetary value of the obligation and the number of shares to deliver increases); and

            ■

              Not inversely related to the underlying stock price or based on something other than Ionis’ stock price.

            o

              These criteria are not applicable for the note hedges because the note hedges represent a right for Ionis to receive cash or shares, not an obligation to issue or repurchase shares.

      Based on the above criteria, we concluded that the note hedges and warrants are not in the scope of ASC 480 and should not be classified as liabilities (or assets) under that guidance. The next step in our accounting
        analysis was to evaluate the note hedges and warrants using the guidance in ASC 815.

            C.

              Whether the note hedges and the warrants meet the conditions to be classified in equity

            i.

              Note Hedges

            1.

              Evaluation of Derivative Definition

      The next part of the accounting analysis for the note hedges required us to determine if the note hedges met the definition of a derivative. We used the guidance in ASC 815-10-15-83, which defines a derivative
        instrument as a financial instrument or other contract with all of the following characteristics:

            •

              Underlying, notional amount, payment provision. The contract has both of the following terms, which determine the amount of the settlement or settlements, and, in some cases, whether or not a settlement is
                required:

            •

              One or more underlyings

            •

              One or more notional amounts or payment provisions or both.

            ➢

              The note hedges met this criterion because:

            o

              The underlying of the note hedges is Ionis’ common stock.

        5

            o

              The notional of the note hedges is a specified number of shares of Ionis’ common stock and/or cash we would receive from the counterparties to the note hedges.

            •

              Initial net investment. The contract requires no initial net investment or an initial net investment that is smaller than would be required for other types of contracts that would be expected to have a similar
                response to changes in market factors.

            ➢

              The note hedges met this criterion because the premium we paid for the note hedges was less by more than a nominal amount than investing in the underlying shares. As such, the premium we paid for the note hedges represented a minimal
                initial net investment.

            •

              Net settlement. The contract can be settled net by any of the following means:

            •

              Its terms implicitly or explicitly require or permit net settlement.

            •

              It can readily be settled net by a means outside the contract.

            •

              It provides for delivery of an asset that puts the recipient in a position not substantially different from net settlement.

            ➢

              The note hedges met these criteria because the note hedges are net share settleable by contract.

      Based on the above criteria, we concluded that the note hedges met the definition of a derivative.

            2.

              Evaluation of Derivative Scope Exception