NEW YORK (AP) — Rafael Nadal's shots were off the mark and, more shockingly, even his boundless energy seemed to fail him. After one miss-hit, the man usually in perpetual motion hunched over, hands on knees, to catch his breath.

No. 2 Nadal and No. 1 Roger Federer will not become the first pair of men to meet in three consecutive Grand Slam finals during a season: Nadal was upset in the U.S. Open quarterfinals by 54th-ranked Mikhail Youzhny of Russia 6-3, 5-7, 7-6 (7-5), 6-1 on Wednesday.

"Unbelievable," Youzhny said. "I cannot believe I beat Rafa in four sets."

He wasn't alone. After all, Youzhny never before had been beyond the fourth round of a major tournament. What was most remarkable was the way Nadal, the two-time French Open champion and this year's Wimbledon runner-up, succumbed at the end, hanging his head at changeovers in the fourth set after wasting a 5-4 lead in the tiebreaker.

"I am trying to fight, but I wasn't," Nadal said. "I was not my best in the fourth, no? I know I lost a big opportunity. And after that, Mikhail is playing unbelievable … all winners."

It was the biggest news on a busy day following Tuesday's almost total rainout. And it's probably safe to say that Youzhny's semifinal opponent — either Andy Roddick or Lleyton Hewitt, two past Open champions who were to meet later Wednesday — would be relieved not to have to face Nadal.

On the other side of the men's draw, the top-seeded Federer moved into a quarterfinal against No. 5 James Blake, both winning in straight sets. That half's other quarterfinal will be No. 7 Nikolay Davydenko against No. 14 Tommy Haas.

"If I play my best, then I don't see any reason why I can't win. If he's playing his best, then I can see a reason why I might not win, but it's possible," said Blake, trying to reach his first major semifinal. "He's lost before. He is human."

Federer lost to Nadal in the French Open final, then returned the favor at Wimbledon.

"I enjoy playing against him, but there's nothing more important to me than winning the tournament in the end," Federer said. "So if I'm in the finals, it doesn't need to necessarily be Nadal. That would just add something more special to it, I guess."

Federer is aiming for major title No. 3 of 2006, but he's also aiming for No. 9 of his career. The two-time defending champion won the first 12 points en route to a 6-3, 7-6 (7-2), 6-3 victory over Marc Gicquel. Blake, meanwhile, saved all 15 break points he faced and eliminated No. 12 Tomas Berdych 6-4, 6-3, 6-1.

"It's a great measuring stick to play the best player in the world," Blake said, looking ahead to facing Federer. "If I beat him, it sure as heck doesn't mean I'm the best player in the world, but maybe for a day, I'll think that."

Youzhny displayed the sort of aggressive and on-the-mark shotmaking he used to knock off No. 6 Tommy Robredo, No. 11 David Ferrer and No. 19 Dominik Hrbaty earlier in the tournament. Before facing Robredo, Youzhny had lost 10 matches in a row against players in the top 10. Before Wednesday, he was 0-6 against players at No. 1 or 2.

But his high-risk style worked to perfection against Nadal. Youzhny compiled more than twice as many winners as Nadal (49-23), limiting Nadal to one in the fourth set.

Youzhny said he needed to play smart to beat Nadal.

"If you play like boom, boom, like a lot of players do, I have no chance," he said. And he revealed something else: Before the tournament, he didn't think he could reach the semifinals.

If the tournament lost some excitement with Nadal's departure, the buzz quotient dropped, too, with 2000 U.S. Open champion Marat Safin's 4-6, 6-3, 2-6, 6-2, 7-6 (7-5) exit against pal and practice partner Haas.

Safin was his usual grumpy self as the match slipped away, throwing his racket to the ground with both hands, letting out yells, muttering to himself. His sister, Safina, let a racket fly, too, but Safin's not about to give her a talking-to about that. He did, however, take credit for her recent rise up the rankings, saying he offered some advice.

And does he heed his own words of wisdom?

"No. When you're 26, it's difficult to change," Safin said. "You can't teach the old dog to sit, huh?"