Fourth seed Stefanos Tsitsipas was stunned by Daniel Galan in the US Open first round, as Daniil Medvedev made a winning start to his title defence.
Tsitispas was one of five players who could have ended the year's final Grand Slam as the top-ranked men's player.
But the Greek, 24, was unable to win any of the first 11 games as he lost in four sets to world number 94 Galan, who prevailed with a ninth match point.
Russian world number one Medvedev beat American Stefan Kozlov 6-2 6-4 6-0.
Medvedev, 26, claimed his first Grand Slam title in New York last year by beating Novak Djokovic, who was not allowed to travel to the United States because he is not vaccinated against Covid-19.
He will play Frenchman Arthur Rinderknech in the second round following his comfortable win on Arthur Ashe Stadium.
Colombian qualifier Galan, meanwhile, faces Australian Jordan Thompson next after securing the biggest win of his career on his main-draw debut at Flushing Meadows in New York.
Although Tsitsipas claimed a must-win third set to keep his hopes alive, Galan was able to recover from a break down in the fourth and won four of the final five games to seal a memorable 6-0 6-1 3-6 7-5 victory.