NEW YORK: Andy Roddick's hopes of a second US Open crown, six years after his first, were blown apart by giant compatriot John Isner in the first major upset of the men's tournament.

The six-foot-nine-inch (2.03m) product of the US collegiate system stunned the fifth seed and top US hope 7-6 (7/3), 6-3, 3-6, 5-7, 7-6 (7/5) in a 3 hours 51 minutes, third-round clash between two of the biggest servers in tennis.

There were scares also for top seed and defending champion Roger Federer and fourth seed Novak Djokovic. Both dropped their opening sets but both bounced back to win in four.

While defending champion and top seed Federer made it 14 in a row over former world No.1 Lleyton Hewitt with a 4-6, 6-3, 7-5, 6-4 win, fourth-seeded Djokovic struggled to see off the challenge of US wildcard Jesse Witten 6-7 (2/7), 6-3, 7-6 (7/2), 6-4.

The Isner-Roddick clash turned on two tie-breaks - one in the first and one in the fifth. Both were won by 24-year-old Isner, who is back to full fitness after missing three months of the year with mononucleosis.

"Maybe I was a little bit fortunate to win tonight, but I played well and I think I deserved it," he said. "It hinged on a few points here and there.

"He brought it back and took it to the fifth set and from there it was anybody's game.

"I told myself, just hold serve, and if I could get to the tie-breaker I was confident.

"I can really do some damage here. I'm not finished yet."

With US No.2 Sam Querrey also going out in a 6-2, 7-5, 6-7 (6/8), 6-1 loss to French Open runner-up Robin Soderling of Sweden, Isner and James Blake, who was playing in the night session, represent the best chance of a first home win since Roddick in 2003.

It was a crushing blow for Roddick, who lost a marathon five-setter to Roger Federer in the Wimbledon final in July.

"It was a tough one to lose especially after coming back all that way," he said.

"Bottom line for the entire match is he played great in the breakers. I dont know if I missed a ball in one of the breakers. He played well when he had to.

Federer, seeking a sixth straight US title to match the 84-year-old record of Bill Tilden, was uncustomarily out first under a hot midday sun at the Arthur Ashe Stadium court and he was uncustomarily sluggish and careless.

In contrast, Hewitt, the champion here in 2001 who is clawing his way back up the rankings after falling out of the top 100 in February, looked much the livlier and more enterprising.

The Australian broke Federer twice to win the first set and had several break points in the third after the Swiss star had levelled the set scores.

But he failed to take them and Federer gradually worked his way back to near his very best, taking the third set and then breaking at start of the fourth.

A consummate front-runner, Federer raced away to clinch his 38th straight win at the US Open, including one walkover, since he lost to David Nalbandian in the fourth round in 2003.

The win, which assures Federer of retaining the world No 1 status no matter who wins the title here, means he will play either Blake or Tommy Robredo of Spain for a place in the quarter-finals.

"It could have gone either way," Federer said.

"He had a good start and he believed maybe more today than in some of the other ones he played against me.

"The way I came through, I was very happy, because 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. So I was relieved coming through."

Djokovic, the 2008 Australian Open champion and 2007 US Open runner-up, took three hours and 28 minutes to subdue Witten, the longest long-shot still in the field at 276th in the world.

"Looking at that match, I don't know who was No. 4 in the world," Djokovic said. "It was a tough win. For either one it would have been well deserved."

Also through early on into the fourth round from the top half of the draw was wily Czech Radek Stepanek, who defeated Germany's Philipp Kohlschreiber 4-6, 6-2, 6-3, 6-3 to set up a clash with Djokovic.

Russian livewire Nikolay Davydenko, seeded eight, cruised past Switzerland's Marco Chiudinelli 6-4, 7-5, 7-5. and he will go up against Soderling.

Spanish 10th seed Verdasco meanwhile hit back from a break down in the final set to edge German veteran Tommy Haas 3-6, 7-5, 7-6 (10/8), 1-6, 6-4.