UNDERWRITING AGREEMENT



                                                               ________ __, 2001



UBS Warburg LLC

Robertson Stephens, Inc.

Needham & Company, Inc.

Fortis Securities Inc.



c/o UBS Warburg LLC

299 Park Avenue

New York, New York  10171-0026





Ladies and Gentlemen:



                  Isis Pharmaceuticals, Inc., a Delaware corporation (the

"Company"), proposes to issue and sell to the Underwriters named in Schedule A

annexed hereto (the "Underwriters") an aggregate of 5,000,000 shares of Common

Stock, $0.001 par value per share (the "Common Stock"), of the Company (the

"Firm Shares"). In addition, solely for the purpose of covering over-allotments,

the Company proposes to grant to the Underwriters the option to purchase from

the Company up to an additional 750,000 shares of Common Stock (the "Additional

Shares"). The Firm Shares and the Additional Shares are hereinafter collectively

sometimes referred to as the Shares. The Shares are described in the Prospectus

which is referred to below.



                  The Company has filed, in accordance with the provisions of

the Securities Act of 1933, as amended, and the rules and regulations thereunder

(collectively, the "Act"), with the Securities and Exchange Commission (the

"Commission") a registration statement on Form S-3 (File No. 333-71176)

including a prospectus, relating to the Shares. The Company has furnished to

you, for use by the Underwriters and by dealers, copies of one or more

preliminary prospectuses (each thereof being herein called a "Preliminary

Prospectus") relating to the Shares. Except where the context otherwise

requires, the registration statement, as amended when it becomes effective,

including all documents filed as a part thereof, and including any information

contained in a prospectus subsequently filed with the Commission pursuant to

Rule 424(b) under the Act and deemed to be part of the registration statement at

the time of effectiveness pursuant to Rule 430(A) under the Act, and also

including any registration statement filed pursuant to Rule 462(b) under the

Act, is herein called the Registration Statement, and the prospectus, in the

form filed by the Company with the Commission pursuant to Rule 424(b) under the

Act on or before the second business day after





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the date hereof (or such earlier time as may be required under the Act) or, if

no such filing is required, the form of final prospectus included in the

Registration Statement at the time it became effective, is herein called the

Prospectus. Any reference herein to the Registration Statement, a Preliminary

Prospectus or the Prospectus shall be deemed to refer to and include the

documents incorporated by reference therein pursuant to Form S-3, and any

reference herein to the terms "amend", "amendment" or "supplement" with respect

to the Registration Statement, any Preliminary Prospectus or the Prospectus

shall be deemed to refer to and include the filing of any document under the

Securities Exchange Act of 1934, as amended, and the rules and regulations

thereunder (collectively, the "Exchange Act") after the effective date of the

Registration Statement, or the Prospectus, as the case may be, deemed to be

incorporated therein by reference.



                  The Company and the Underwriters agree as follows:



                  1.       SALE AND PURCHASE. Upon the basis of the

representations and warranties and subject to the terms and conditions herein

set forth, the Company agrees to sell to the respective Underwriters and each of

the Underwriters, severally and not jointly, agrees to purchase from the Company

the respective number of Firm Shares set forth opposite the name of such

Underwriter in Schedule A annexed hereto in each case at a purchase price of

$____ per Share. The Company is advised by you that the Underwriters intend (i)

to make a public offering of their respective portions of the Firm Shares as

soon after the effective date of the Registration Statement as in your judgment

is advisable and (ii) initially to offer the Firm Shares upon the terms set

forth in the Prospectus.



                  In addition, the Company hereby grants to the several

Underwriters the option to purchase, and upon the basis of the representations

and warranties and subject to the terms and conditions herein set forth, the

Underwriters shall have the right to purchase, severally and not jointly, from

the Company, ratably in accordance with the number of Firm Shares to be

purchased by each of them, all or a portion of the Additional Shares as may be

necessary to cover over-allotments made in connection with the offering of the

Firm Shares, at the same purchase price per share to be paid by the Underwriters

for the Firm Shares. This option may be exercised by you on behalf of the

several Underwriters at any time and from time to time on or before the 30th day

following the date hereof by written notice to the Company. Such notice shall

set forth the aggregate number of Additional Shares as to which the option is

being exercised and the date and time when the Additional Shares are to be

delivered (such date and time being herein referred to as the additional time of

purchase); PROVIDED, HOWEVER, that the additional time of purchase shall not be

earlier than the time of purchase (as defined

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