NEW YORK -- Andy Roddick's U.S. Open is over much sooner than he expected.
Coming off a close-as-could-be loss in the Wimbledon final, Roddick came to Flushing Meadows with a rebuilt game and some serious self-belief. Running into strong-serving, 6-foot-9 American John Isner in the third round proved to be too much to handle.
The 55th-ranked Isner smacked 38 aces to beat the No. 5-seeded Roddick 7-6 (3), 6-3, 3-6, 5-7, 7-6 (5) Saturday.
"It's obviously, hands down, the biggest win of my career. Nothing even compares. To do it at the stage I did it on is pretty spectacular. Maybe it will sink in a little bit more tomorrow," said Isner. "But I know I can really do some damage here. So I'm not satisfied just yet."
It's the first time Isner has reached the fourth round at a Grand Slam tournament. Roddick, in contrast, won the 2003 U.S. Open and has been the runner-up at a major four times, most recently at the All England Club in July.
"It's tough. I mean, I don't know if I've come to a tournament with as much confidence -- into a Slam -- as I did with this tournament," Roddick said. "Leaving earlier than I want to."
His loss marked the first significant upset of Week 1 of the men's tournament: The men seeded No. 1 through No. 16 were 38-0 before Roddick and Isner stepped on court.
Federer took a spill in his Saturday afternoon match, but rebounded to defeat No. 31 Lleyton Hewitt 4-6, 6-3, 7-5, 6-4 to extend his winning streak to 37 matches at Flushing Meadows -- and 14 straight over his Aussie rival, the 2001 U.S. Open champion.
Perfect it was not.
Federer was serving, ahead 4-2 and 40-love in the first set, when he proceeded to spray shots all over the court at Arthur Ashe Stadium, losing five straight points on the way toward dropping the first set. He committed 23 unforced errors in the first.
"I just had to believe that I could still turn this around," Federer said. "And with the great streak I have against him, I knew that if I could get back into the match then I could get back on a roll, because I've done it so many times against him."
Yet even when he looked to be cruising to the victory in the closing set, up 5-2 and getting ready to serve out the match, he got broken. All that did was extend the match a few more minutes, though it did nothing to quash the notion that Federer was not at the top of his game on this day.
"You know how good he can play when he's on and you try to take advantage of those small opportunities when they come," Hewitt said. "You're not going to get a lot, obviously."
Hewitt did have four break points in the third set, but couldn't convert any.
Hewitt, a two-time major winner, won eight of the first 10 meetings in his series against Federer. But that was years ago, before Federer started winning Grand Slam tournaments with regularity, and before Hewitt started enduring hip problems that dropped him out of the top 100 before his more recent resurgence.
"I knew that being down a set against Lleyton is always going to be a difficult situation for me to be in: Make one more mistake and I'm in the fifth set, maybe, or I go down completely," said Federer. "So I was relieved coming through."
Federer is trying to become the first player to win six straight titles in New York since Bill Tilden in the 1920s.
Other winners on the men's side included 15th-seeded Radek Stepanek, eighth-seeded Nikolay Davydenko and fourth-seeded Novak Djokovic, who ended 276th-ranked American Jesse Witten's surprising run. Also gone is 22nd-seeded Sam Querrey, a 6-2, 7-5, 6-7 (6), 6-1 loser to No. 12 Robin Soderling.
Witten is the University of Kentucky graduate who brought five of his buddies to New York, cramming everyone in his Manhattan hotel room, figuring he'd last in the main draw only for a night or two. Instead, the visit lasted a week and the 276th-ranked player also put a scare into Djokovic, the 2008 Australian Open winner, in a 6-7 (2), 6-3, 7-6 (2) 6-4 loss that lasted nearly 3 1/2 hours.
"My biggest thing usually is I feel like I don't belong," Witten said. "It's good to see I can play with these guys and belong a little bit on the stage. Hopefully, I can stay around a little longer.
"I wasn't getting outplayed too much," said Witten, 0-6 in tour-level matches before this week. "I felt like I was right at home a little bit."
Perhaps what bothered Roddick the most was that he played quite well Saturday.
He broke Isner's serve twice and was only broken once himself. His groundstrokes were clean, with only 20 unforced errors -- 32 fewer than Isner. And then there was this little detail: Roddick won 162 points, Isner 155.
But Isner came through in the tiebreakers.
"I mean, there's a lot that's out of your hands with the way he plays. I said it before: You can't really teach 6-9, especially coming down on a serve," Roddick said. "You try to fight it off as much as you can. Sometimes you can, and sometimes it's completely out of your hands."
How does Isner do so well in such pressure-packed situations?
Particularly against a player, in Roddick, who tends to be as good as it gets in tiebreakers.
"Never panicked. If I lose that match, I have nothing to hang my head about. Played well. Maybe a little bit more the pressure's on him. He's expected to do so well here," Isner said. "Nobody expected me to win."
Isner -- who led Georgia to the 2007 NCAA team tennis championship -- lost in the first round at five consecutive major tournaments until this one. He missed three months this season from mid-April to mid-July with mononucleosis, but Saturday's victory will push him into the top 50 in the rankings.
"I was watching the French Open. I remember how ticked off I was at home," Isner said. "But I think it might have been a blessing in disguise."
Now Isner owns his first victory over Roddick in three meetings.
Now he moves on, facing No. 10 Fernando Verdasco of Spain with a quarterfinal berth at stake.
As for Roddick?
His quest for a second Grand Slam title will have to be postponed until next season.
And this defeat at a major tournament doesn't feel anything like that 16-14 fifth set against Federer at Wimbledon.
"It's different. I wasn't anywhere close to winning this tournament yet," Roddick said. "There's not another chance a month and a half away."
The Associated Press contributed to this story.