Former champion Venus Williams has pulled out of the US Open saying she is battling an illness that causes fatigue and joint pain.
The American had been due to play Germany's Sabine Lisicki in round two but withdrew because of the illness.
"I have been recently diagnosed with Sjogren's Syndrome," said Williams, who won the title in 2000 and 2001.
"It is an ongoing medical condition that affects my energy level and causes fatigue and joint pain."
The 31-year-old continued: "I enjoyed playing my first match here and wish I could continue, but right now I am unable to.
"I am thankful I finally have a diagnosis and I am now focussed on getting better, and returning to the court soon."
Williams had pulled out the US Open build-up tournaments in and Cincinnati earlier this summer because of a virus, and was playing in just her fourth tournament of 2011.
The two-time former champion came into the tournament not having played since because of the illness, which she had not named until now, but managed to beat Vesna Dolonts on Monday.
Nineteen-year-old American Christina McHale pulled off the biggest upset on Wednesday as she took out number eight seed Marion Bartoli of France 7-6 (7-2) 6-2.
Bartoli, who has now fallen in the second round in New York for three years running, broke McHale's serve in the opening game but the American fought back impressively.
McHale, who came into the US Open with a career-high number 55 ranking, and now moves into the third round of a major for the first time in her career.
"I'm so excited to have beaten a player like Marion, especially to have it happen here at the US Open," she said.
And Bartoli, considered by many as a serious title contender, admitted: "I think I played a fairly good match, but she deserved to win. She was on fire. She played the prefect match. She moved so well - I had to hit five or six winners to win one point."
In the night session, third seed Maria Sharapova was in terrific form as she swept past Anastasiya Yakimova 6-1 6-1 in just 70 minutes, with the match finishing at just past midnight in New York.
Number two seed Vera Zvonareva earlier progressed to the third round with a hard-fought 7-5 3-6 6-3 win over Kateryna Bondarenko.
"I didn't play my best tennis, but I managed to get through this one," said the Russian. "I gave myself another chance to go out there and try to do a little bit better."
Zvonareva, who lost to Kim Clijsters in last year's final, next faces Anabel Medina Garrigues, seeded 30th, .
Australia's ninth seed Sam Stosur beat American Coco Vandeweghe 6-3 6-4, while Irina Falconi of the US knocked out Slovakian 14th seed Dominika Cibulkova 2-6 6-3 7-5.