Two-time winner Naomi Osaka has joined defending champion Emma Raducanu as prominent first-round casualties in the US Open women's field.
Wimbledon champion Elena Rybakina and seven-time grand slam winner Venus Williams also crashed out in the opening round.
The first qualifier to win a grand slam title last year, 19-year-old Raducanu was beaten 6-3 6-3 by French veteran Alize Cornet in Louis Armstrong Stadium on Tuesday night.
She became only the third woman to lose her opening match in New York a year after winning the title - joining 2004 champion Svetlana Kuznetsova and 2016 champion Angelique Kerber.
She was bothered by hand blisters but simply outplayed by 32-year-old Cornet, who had ended world No.1 Iga Swiatek's 37-match winning streak at Wimbledon.
"Obviously really disappointing. Really sad to leave here. It's probably my favourite tournament," said Raducanu.
"But also, I mean, in a way, (I'm) happy, because it's a clean slate. I'm going to drop down the rankings, climb my way back up."
Osaka, who won two of her four Grand Slam titles in New York, was eliminated by Australian Open runner-up Danielle Collins 7-6 (5), 6-3 in a match that ended after midnight.
Osaka, a former No. 1, also lost in the first round of the French Open this year and has slid to 44th in the rankings.
She had been 3-0 head-to-head against Collins.
Rybakina was upset 6-4 6-4 by French qualifier Clara Burel, who is ranked 131st in the world.
Rybakina was seeded only 25th, with her victory at Wimbledon not boosting her in the rankings because no points were awarded at the All England club this year after Russian and Belarusian players were barred from competing because of the war against Ukraine.
Rybakina, who was born in Russia but represents Kazakhstan, said before this tournament she thought that was unfair, adding she didn't even feel like a Wimbledon champion.
The welcome and support for Venus Williams at Arthur Ashe Stadium was not the same as they were for her sister, Serena, a night earlier. Nor was the result.
She lost 6-1 7-6 (7-5) to unseeded Belgian Alison Van Uytvanck.
Venus, who turned 42 in June, has not made any pronouncements about her future in tennis, unlike her younger sibling, and while she has been successful and influential, too, the fanfare and attention are not the same.
Playing in front of thousands of empty blue seats, Venus bowed out in the first round of the US Open for the second consecutive appearance, losing in straight sets.
This was the 23rd trip to Flushing Meadows for Venus, who made it to the final in 1997 as a teen then won the trophy in 2000 and 2001, and her record 91st time participating in a major tournament.
She was off the tour in singles entirely from August 2021 until less than a month ago and is now 0-4 since her return. Her ranking - which 20 years ago was No.1 - is 1504 this week.
Meanwhile, world No.1 Swiatek had no problems in progressing, swatting away Jasmine Paolini 6-3 6-0.
The Polish star is chasing a third slam title, and her second of the year after triumphing at the French Open in June.
Swiatek is likely to face a more difficult challenge in the next round when she runs into 2017 champion Sloane Stephens, who battled back to see off Belgium's Greet Minnen 1-6 6-3 6-3.
Also through is American eighth seed Jessica Pegula, who beat Viktorija Golubic 6-2 6-2, and sixth-seeded Belarusian Aryna Sabalenka after her 6-1 6-3 win over Catherine Harrison.
Garbine Muguruza of Spain, seeded ninth, beat Clara Tauson 6-3 7-6 (7-5).
Karolina Pliskova, the 2016 US Open runner-up and No.22 seed, needed a third-set tiebreaker to edge Magda Linette, but 16th seed Jelena Ostapenko was ousted by China's Zheng Qinwen.