Fourth seed Nishikori, who last year became the first Asian man to reach a grand slam final, found defeat hard to swallow after squandering two match points in the 6-4 3-6 4-6 7-6(6) 6-4 loss to Frenchman Benoit Paire.
The 25-year-old Japanese had plenty of company at the exit following a string of opening-day upsets that included Serbian seventh seed and former world number one Ana Ivanovic, eighth seeded Czech Karolina Pliskova and 10th-seed Carla Suarez Navarro of Spain.
A hot, muggy day that attracted a record first session crowd of over 37,000 got off to an ominous start when 50th-ranked Slovakian Dominika Cibulkova dispatched Ivanovic 6-3 3-6 6-3 on the Arthur Ashe Stadium court.
Anna Tatishvili gave the home fans a reason to get excited as the 121st-ranked American qualifier destroyed Pliskova 6-2 6-1 while Frenchwoman Oceane Dodin kept the upsets trending with 2-6 7-5 6-3 victory over Jelena Jankovic, the 21st seed and 2008 U.S. Open runner-up.
It was Nishikori, however, who generated the opening day buzz as his hopes of making another magical U.S. Open run came to a quick end.
Marin Cilic, who beat Nishikori in last year’s final, had no opening day hiccups as the ninth-seeded Croat began defence of his title with a 6-3 7-6(3) 7-6(3) win over Argentine qualifier Guido Pella.
Recovering from a wobbly first set Nishikori had looked ready to survive the opening test taking a 6-4 lead in the fourth set tiebreak.
But the 41st-ranked Paire would fight off two match points then take the tiebreak and carry the momentum into the fifth set where he recorded the decisive break to go up 3-2 before finishing off Nishikori with a booming ace.
“It’s always very sad to lose in the first round, but I think he was playing good tennis,” said Nishikori. “I don’t think I played badly. Didn’t play great, but still, it’s never easy first match.”
Venus Williams, a two-time U.S. Open champion, scrapped to a centre court 6-4 6-7(7) 6-3 win over Puerto Rico’s Monica Puig hours before sister and world number one Serena launches her bid to complete a calendar year sweep of the grand slams against Russia’s Vitalia Diatchenko.
(Editing by Frank Pingue)