The 74-year-old Pulitzer Prize-winning columnist will write his last op-ed column on Jan. 24, 2005.
"After more than three decades of opinionated reporting on the world's first and foremost political battle page, it's time to hang up my hatchet," Safire said in a statement released by the Times. "The Times said at the start of this run that it wanted 'another point of view,' which was what it surely got."
Safire's commentary has held Times' readers captivated since his first op-ed piece appeared in 1973, Publisher Arthur Sulzberger Jr. said.
"Reaching for his column became a critical and enjoyable part of the day for our readers across the country and around the world," Sulzberger said in a statement. "Whether you agree with him or not was never the point. His writing is delightful, informed and engaging."
A successor has not been chosen, according to the Times.
The paper said Safire will continue to write his "On Language" column, which has appeared in its Sunday magazine since 1979 and spawned 15 books by Safire.
Safire won the Pulitzer Prize for distinguished commentary in 1978; he has served on the Pulitzer board since 1995.
Before joining the Times as a political columnist, Safire was senior White House speechwriter for President Nixon. He began his career in 1949 as a reporter for a profiles column in the New York Herald Tribune.
Besides his language books, Safire has written 10 works of fiction and nonfiction and edited five anthologies.
Safire currently is chairman of the Dana Foundation, a philanthropy supporting brain science, immunology and arts education. He has been involved in the organization since 1993, and now plans to make it his principal occupation, the Times said.
By Pat Milton