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Born to a Jewish family with Romanian roots on his father's side whose last name was originally "Safir", William Safire later added the "e" for pronunciation reasons, though some of his relatives continue to use the original spelling. Safire graduated from the Bronx High School of Science, a specialized public high school in New York City. He attended Syracuse University but dropped out after two years. He would deliver the commencement address at Syracuse in 1978 and 1990 and become a trustee of the university.

He was a public relations executive from 1955 to 1960. Previously, he had been a radio and television producer and a United States Army correspondent. He worked as a publicist for a homebuilder who exhibited a model home at an American trade fair at Sokolniki Park in Moscow in 1959...the one in which Richard Nixon and Nikita Khrushchev had their famous "Kitchen Debate". A widely circulated black-and-white picture of the event was photographed by Safire. Safire subsequently joined Nixon's campaign for the 1960 Presidential campaign, and again for the 1968 campaign. After Nixon's 1968 victory Safire served as a speechwriter for him and Spiro Agnew; he is well known for having created Agnew's famous term, "nattering nabobs of negativism".

He joined the New York Times as a political columnist in 1973. Soon after joining the Times, Safire learned that he had been the target of "national security" wiretaps authorized by Nixon, and, after noting that he had worked only on domestic matters, wrote with what he characterized as "restrained fury" that he had not worked for Nixon through a difficult decade "to have him...or some lizard-lidded paranoid acting without his approval...eavesdropping on my conversations."

In 1978, Safire won the Pulitzer Prize for commentary on Bert Lance's alleged budgetary irregularities.

Safire also frequently appeared on the NBC's Meet the Press.

Upon announcing the retirement of Safire's political column in 2005, Arthur Sulzberger Jr., publisher of The New York Times, stated:

The New York Times without Bill Safire is all but unimaginable, Bill's provocative and insightful commentary has held our readers captive since he first graced our Op-Ed Page in 1973. Reaching for his column became a critical and enjoyable part of the day for our readers across the country and around the world. Whether you agreed with him or not was never the point, his writing is delightful, informed and engaging.

Safire served as a member of the Pulitzer Board from 1995. After ending his op-ed column, he became the full-time chief executive of the Dana Foundation where he was chairman from 2000. In 2006, Safire was awarded the Presidential Medal of Freedom by President George W. Bush.

Portions of Safire's FBI file were released in 2010. The documents "detail wiretapping ordered by the Nixon administration, including the tapping of Safire's phone."

Safire described himself as a "libertarian conservative". A Washington Post story on the ending of his op-ed column quotes him on the subject:

I'm willing to zap conservatives when they do things that are not libertarian. [After the 9/11 attacks,] I was the first to really go after George W. on his treatment of prisoners.

After voting for Bill Clinton in 1992, Safire became one of the leading critics of Clinton's administration. Hillary Clinton in particular was often the target of his ire. He caused controversy when he called her a "congenital liar"; she responded that she didn't feel offended for herself, but for her mother's sake. According to the president's press secretary at the time, Mike McCurry, "the President, if he were not the President, would have delivered a more forceful response to that on the bridge of Mr. Safire's nose".

Safire was one of several voices who called for war with Iraq, and predicted a "quick war", with Iraqis cheering their liberators. He consistently brought up the point in his Times columns that an Iraqi intelligence agent met with Mohamed Atta, one of the 9/11 attackers, in Prague, a theory which was debunked by the CIA and other intelligence agencies. Safire insisted that the theory was true and used it to make a case for war against Iraq. Safire also wrote that "freed scientists" would lead coalition forces to "caches [of weapons of mass destruction] no inspectors could find". Safire never retracted his comments.

Safire was staunchly pro-Israel. He received the Guardian of Zion Award of Bar-Ilan University in 2005. President George W. Bush appointed him to serve on the Honorary Delegation to accompany him to Jerusalem for the celebration of the 60th anniversary of the State of Israel in May 2008.

In addition to his political columns, Safire wrote a column "On Language" in the weekly New York Times Magazine from 1979 until the month of his death. Many of the columns were collected in books. According to the linguist Geoffrey Pullum, over the years he became less of a "grammar-nitpicker", and Benjamin Zimmer cited his willingness to learn from descriptive linguists. Another book on language was The New Language of Politics (1968), which developed into what Zimmer called Safire's "magnum opus", Safire's Political Dictionary.

Safire died from pancreatic cancer at a hospice in Rockville, Maryland, on September 27, 2009, aged 79. He is survived by his wife Helene; their children Mark and Annabel; and granddaughter Lily.

The following is a partial list of his writings:

Language

• The Right Word in the Right Place at the Right Time: Wit and Wisdom from the Popular Language Column in the New York Times Magazine (2004) ISBN 0-7432-4244-0
• No Uncertain Terms: More Writing from the Popular "On Language" Column in The New York Times Magazine (2003) ISBN 0-7432-4243-2

Novels

• Scandalmonger (2000) ISBN 0-684-86719-2
• Sleeper Spy (1995) ISBN 0-679-43447-X
• Freedom: A Novel of Abraham Lincoln and the Civil War (1987) ISBN 0-385-15903-X
• Full Disclosure (1978) ISBN 0-385-12115-6
• The First Dissident -The Book of Job in Today's Politics; Random House 1992;ISBN 0-679-74858-x
• Lend Me Your Ears: Great Speeches in History (1997) ISBN 0-393-04005-4
• Words of Wisdom: More Good Advice (1989) ISBN 0-671-67535-4
• Good Advice (1982) quotations compiled with his brother, Leonard Safir ISBN 0-517-08473-2

Political works

• Safire's Political Dictionary, 3rd edition, Random House, NY, 1968, 1972, 1978. ISBN 0394502612
• The Relations Explosion
• Plunging into Politics
• Before the Fall: An Inside View of the Pre-Watergate White House
• The First Dissident: The Book of Job in Today's Politics, Random House, NY, 1992

Speeches

• In Event of Moon Disaster, a presidential speech Safire wrote (but Nixon never delivered)