Williams, 31, on Wednesday said in a statement she had recently been diagnosed with Sjogren’s Syndrome “which affects my energy level and causes fatigue and joint pain.”
Williams had pulled out of two US Open tune-up events because of illness, but had hoped to get back on track at the Grand Slam she won in 2000 and 2001.
“I enjoyed playing my first match here and wish I could continue, but right now I am unable to,” said the American star who had been due to tackle Wimbledon semi-finalist Sabine Lisicki in Wednesday’s second round.
“I am thankful I finally have a diagnosis and am now focused on getting better and returning to the court soon.”
Williams’ news comes as her younger sister Serena, a 13-time Grand Slam champion, is working her way back from a series of health issues that sidelined her for 11 months.
Two hardcourt victories this summer have established Serena as a favorite here, where a wide open women’s draw features two top seeds who have never won a Grand Slam.
That includes second-seeded Russian Vera Zvonareva, who led the way into the third round with a 7-5, 3-6, 6-3 victory over 53rd-ranked Ukrainian Kateryna Bondarenko.
Zvonareva, beaten by Kim Clijsters in the final at Flushing Meadows last year, survived 46 unforced errors to claim the win.
After dropping the second set, she bore down to take a 4-1 lead and finally finished off the tenacious Bondarenko on her third match point.
“It was a good test for me,” Zvonareva said. “I wouldn’t say I’m pleased with the quality of tennis I showed, but I’m pleased the way I handled the match.”
Third-seeded Russian Maria Sharapova, seeking to build on her run to the Wimbledon final, powered past 84th-ranked Anastasiya Yakimova of Belarus 6-1, 6-1.
Sharapova was on court just 70 minutes, wrapping it up shortly after the clock passed midnight.
“It only gets tougher from here, but that’s what’s so special about being the winner at the end of the tournament,” Sharapova said. “It’s a road.”
French Open semi-finalist Marion Bartoli found her road blocked by US teenager Christina McHale.
McHale, 19 and ranked 55th in the world, fired an ace past the Frenchwoman to seal a 7-6 (7/2), 6-2 victory.
McHale wasn’t the only American youngster to shine on Wednesday.
Irina Falconi, 21, trailed 0-3 in the third set but rallied for a 2-6, 6-3, 7-5 victory over 14th-seeded Dominika Cibulkova.
Jack Sock, the 18-year-old wildcard who won the US Open junior title last year, defeated France’s Marc Gicquel 6-4, 6-3, 1-6, 6-4 to reach the men’s second round.
Sock next faces Andy Roddick, a former world number one who has been struggling this summer as he hit his 29th birthday on Tuesday.
Roddick looked unexpectedly defensive against compatriot Michael Russell but prevailed 6-2, 6-4, 4-6, 7-5.
World number four Andy Murray got off to a slow start, but booked his second-round berth with 7-6 (7/5), 6-2, 6-3 victory over India’s Somdev Devvarman.
Murray needed more than an hour to secure the first set against Devvarman, but needed little more than that to wrap up the next two sets and get his bid for a first Grand Slam title off and running.
Since reaching the final here in 2008, Murray has failed to make the quarter-finals the past two years, a trend he’s hoping to reverse.
Juan Martin del Potro made a triumphant return to Flushing Meadows, routing Italian Filippo Volandri 6-3, 6-1, 6-1 in his first US Open match since he lifted the 2009 trophy.
Del Potro, seeded 18th, was unable to defend his title last year as he recovered from a wrist injury that sidelined him from January to Setpember of 2010.
This season the Argentinian has been steadily rebuilding his ranking, winning titles at Delray Beach and Estoril and reaching the semi-finals in three other tournaments.
Men’s sixth seed Robin Soderling withdrew before his scheduled first-round match against Louk Sorensen.
Lucky loser Rogerio Dutra Da Silva took his place in the draw and defeated Sorensen when the Irish qualifier retired while trailing in their match.
Da Silva was up 6-0, 3-6, 6-4, 1-0 when Sorensen bowed out, becoming the second Irishman to call it quits early after ailing Conor Niland retired while trailing world number one Novak Djokovic on Tuesday.