Former US Open champion Dominic Thiem has been bundled out at Flushing Meadows in the first round by Pablo Carreno Busta 7-5 6-1 5-7 6-3 on Monday.
The Austrian, who was back to defend his 2020 title after missing last year due to a wrist injury, was no match for the 12th-seeded Spaniard, despite coming in with a 7-0 head-to-head record.
Four-time Grand Slam finalist Thiem has struggled for the past 14 months, with a mix of injury and form, only gaining entry at the US Open with a wild card.
Thiem is now ranked 211th in the world and has a 9-10 record this season, albeit with an improved past two months.
Former world number three Thiem had waited 426 days between ATP Tour level wins, when he triumphed at the Swedish Open in July this year.
Carreno Busta, who won in Montreal earlier this month, won in three hours and 18 minutes, rallying back from a 2-4 deficit early to peel off 10 of the next 11 games and claim a two-set lead.
Thiem responded in the third set by breaking in the second game, with Carreno Busta committing more unforced errors, but the Austrian could not maintain the pressure in the fourth.
The Austrian hit 44-31 winners but was not helped by unforced errors (54-32), while his first serve percentage was down at 59 per cent, winning only 58 per cent on his first serve.
"I think everybody who thought that I was the favourite today was far away from reality," Thiem told reporters.
"Pablo has a great season. He won Montreal. He's a two-times semifinalist here. I'm just still in the process of coming back. I'll take a lot of good things from today and going to move on."