Marat Safin's bid for a second US Open title lasted just two hours, 37 minutes as he lost 7-6
6-4 3-6 6-3 by Thomas Enqvist of Sweden in the first round.
The 13th-seeded Russian, who won the 2000 US Open, hit 17 aces but was outplayed by the 30-year-old Swede on the way to his earliest exit from the tournament in six visits.
Having reached the Australian Open final in January on a similar surface, Safin was considered one of the favourites for the title.
But after twice failing to serve out the first set, Safin lost it on a tiebreak and Enqvist took the second set thanks to one service break.
Safin gave his supporters hope of a comeback when he came from 3-1 down to win the third set, but after missing a breakpoint in the opening game of the fourth set, he then lost his serve in the next game and Enqvist served out for victory.
The Swede will face American wildcard Bobby Rena or Austrian qualifier Alexander Peya in the second round.
Meanwhile, fifth seed Tim Henman withstood a barrage of aces before taming giant Croat Ivo Karlovic 7-6 6-7 4-6 6-4 6-4.
Karlovic, at 2.08 metres (six feet 10 inches) the tallest player on tour, blasted 39 aces past the Briton who squandered two set points for a two-set lead and was slipping towards defeat when he lost the third set to trail 2-1.
But Henman, who lost to Andy Roddick in the first round last year, refused to buckle. The 29-year-old broke early in the fourth set and repeated the trick in the fifth before claiming victory in three hours, 37 minutes.
Henman, still waiting for his first grand slam title, meets Jerome Golmard in the second round after the Frenchman beat Georgia's Irakli Labadze in four sets.