Seven-time grand slam champion Venus Williams made her second consecutive US Open second-round exit as German sixth seed Angelique Kerber ousted the American 6-2, 5-7, 7-5.
The loss made this the first year in Williams' pro career, which began in 1997, that she has not gone past the second round in any grand slam tournament.
"Losing a match like this isn't a lot of fun, but that's sport," Williams said. "All I had was fight because I didn't play well."
Kerber, a 24-year-old left-hander who advanced to the semi-finals last month at Wimbledon and at last year's US Open, reached a third-round date with Olga Govortsova, of Belarus, who beat British qualifier Johanna Konta 2-6, 6-2, 7-5.
"It's unbelievable," Kerber said. "I had great memories from last year and the match was so tough and so close. Venus won so many grand slams and I'm so happy to beat her in New York. It's an amazing feeling to play here in a night session."
Kerber improved to 19-2 in three-set matches this year, helped by 16 double faults and 60 unforced errors from Williams.
"I was trying hard but I was making errors everywhere," Williams said. "I made 60 errors. It's hard to win a match like that."
Williams, whose most recent major title came in 2008 at Wimbledon, missed a chance to avenge a third-round loss to Kerber at the London Olympics.
Kerber, who had five double faults and 25 unforced errors, also beat Williams' sister Serena in a Cincinnati quarter-final to snap the 14-time grand slam champion's 19-match win streak that included Wimbledon and Olympic titles.
"I just tried to play my game plan, fighting every point to the last," Kerber said.
"It's amazing that I've won so many third sets this year. I will try to stay focused and continue this in the next months."
Williams, ranked 46th, battles an auto-immune ailment that saps her energy. She has not won a title since Acapulco in 2010 and has not lifted a US Open trophy since her back-to-back crowns in 2000 and 2001.
"If I could make two more shots I probably could have won that match," said Williams. "I was extremely aggressive but it's hard to be aggressive when every shot you go for goes out.
"I'm not getting destroyed out there. I have to find the answer inside myself."