The 31-year-old American has won seven Grand Slam titles, including at Flushing Meadows in 2000 and 2001.
"I enjoyed playing my first match here, and wish I could continue but right now I am unable to," Williams said in a statement released by the tournament. "I am thankful I finally have a diagnosis and am now focused on getting better and returning to the court soon."
She was supposed to face 22nd-seeded Sabine Lisicki in the second round Wednesday.
Williams cited a virus when withdrawing from hard-court tuneup tournaments since losing in the fourth round at Wimbledon in late June.
She returned to action Monday, beating Vesna Dolonts 6-4, 6-3 in the first round in New York, then said: "No one is more in one-match-at-a-time mode than me now at this tournament. It will just be one match at a time, for sure."
According to the Sjogren's Syndrome Foundation website, the disease is a chronic autoimmune illness in which people's white blood cells attack their moisture-producing glands. Common symptoms include dry eyes and dry mouth. As many as 4 million Americans have the disease.
In rare cases, it can cause arthritis and joint pain, said Dr. John Fitzgerald, director of clinical rheumatology at UCLA. Fitzgerald is not involved in treating Williams and does not know her symptoms or medical history. But, he said, if Williams has the typical symptoms, "it does not seem life-threatening or career-ending."
Williams arrived at the Billie Jean King National Tennis Center on Wednesday hours before her match was scheduled to begin and tried warming up by hitting balls.
When Williams left the site shortly before 5 p.m., wearing a white sweater and purple shorts, she was asked by reporters whether she would say anything. She smiled and waved and shook her head to indicate, "No," then climbed into the back of a tournament transportation car and rode away.
"All of us came with the full expectation she'd be playing today. She was geared up to play her match," said Williams' agent, Carlos Fleming.
"I just hope she's OK," Fleming added, "and I hope she's healthy and going to be fine."
Despite all of her past success, including a brief stint at No. 1 in the rankings, Williams was unseeded at the U.S. Open, because she has fallen to 36th after a year of little action. Since reaching the semifinals at last year's U.S. Open, Williams has played only 11 matches, and the WTA projects that her ranking now will slide out of the top 100.
Her younger sister, Serena, a 13-time Grand Slam champion, is scheduled to play her second-round match Thursday.
"A lot of times, they've drawn a lot of criticism. But, trust me, (in) five years, when they're gone, everyone is going to miss them. Everyone is going to realize they're going to be living legends for the rest of their lives. Two girls from Compton, dominating tennis — that's not an everyday story," said 2003 U.S. Open champion Andy Roddick, who's known the Williams sisters for about two decades.
"Venus is just the epitome of class, the way she's gone about it," he said. "I don't think she's ever even had a sniff of controversy around her. She's just done it the right way."
On Monday, Venus Williams was asked about the illness that caused her to skip tournaments this summer. She said that night that her ailment had been diagnosed, but wouldn't say what it was.
"It was just energy-sucking, and I just couldn't play pro tennis," she said Monday. "It was disappointing, because I had huge plans for this summer, of course, to improve my ranking. To miss out on all those points was definitely devastating. Just to miss so much time off tour was just disheartening. But I'm just really excited to be back."
Lisicki said she saw Venus Williams on the practice courts and in the locker room and expected to play their match — until the tournament referee passed along the news of the withdrawal.
"She's a tough girl, and I think she'll come back. You know, it would be unfortunate if she couldn't," Lisicki said. "Serena and Venus both are amazing players, and it's nice to have them in the women's sport. I hope she comes back."