Serena Williams withdrew from the U.S. Open on Friday, saying she is still recovering from surgery to repair cuts on her right foot.
The top-ranked Williams has won three titles at Flushing Meadows, part of her 13 Grand Slam singles championships, the most among active women.
Last year, she lost in the U.S. Open semifinals after a tirade at a line judge over a foot-fault call, an outburst that drew a record fine.
"It is with much frustration and deep sadness that I am having to pull out of the U.S. Open," Williams said in a statement released by her publicist.
Williams said doctors advised her not to play so her foot can heal, and she called missing the tournament "one of the most devastating moments of my career."
The 28-year-old American was reportedly hurt by a broken glass at a restaurant while she was in Munich last month -- shortly after winning her fourth Wimbledon singles title on July 3 and before playing in an exhibition match against Kim Clijsters that drew a tennis-record crowd of 35,681 in Brussels on July 8.
Williams had surgery in Los Angeles on July 15. She had already pulled out of three hard-court tournaments she was scheduled to enter in preparation for the U.S. Open and also skipped playing World TeamTennis.
Williams' withdrawal also means she won't team with older sister Venus to defend the doubles title they won in New York last year. Venus, who hasn't competed on tour since Wimbledon because of a bothersome left knee, is expected to play singles at Flushing Meadows.
Andy Roddick, the 2003 U.S. Open champion, said Williams' absence is a "fairly big-sized hit for the tournament."
"I haven't had a chance to talk to her about it, but I do know the U.S. Open is probably her favorite event, so obviously, if she's this far out and is not going to play, it's got to be something pretty serious, which is unfortunate," Roddick said, "because there's no doubt about who the top draw card is in New York City as far as the women's side of the draw."
Later Friday, No. 10 Jo-Wilfried Tsonga and three-time U.S. Open quarterfinalist Tommy Haas withdrew from the tournament. Carlos Berlocq of Argentina and Dudi Sela of Israel replaced them in the main draw.
Williams has participated in the last 16 major tournaments; the last one she missed was Wimbledon in 2006.
She won her first Grand Slam singles championship at the 1999 U.S. Open and also took home the trophy from New York in 2002 and 2008.
But in 2009, Williams lashed out at a lineswoman during her semifinal against eventual U.S. Open champion Clijsters. It was a profanity-laced, finger-pointing, racket-brandishing display during which Williams approached the official with what tournament director Jim Curley called at the time "a threatening manner."
About 2˝ months later, Williams was fined $82,500 by the Grand Slam administrator and told she would be suspended from the U.S. Open if she has another "major offense" at any Grand Slam tournament in 2010 or 2011.
Both of Williams' titles this season came at major championships: the Australian Open and Wimbledon.
If healthy, she would have been considered the favorite at the U.S. Open, where play starts Aug. 30.
"We regret that Serena Williams is unable to play the U.S. Open and wish her a speedy recovery," Curley said Friday. "She will be missed, but the tournament is about the competition and the players on the court."
Five-time U.S. Open champion Roger Federer said Williams' withdrawal has "got to be disappointing for her and for the tournament. I'm sure it hurts, especially with her being an American."