The 31-year-old American, the champion at Flushing Meadows in 2000 and 2001, played her first match in two months Monday, when she beat Vesna Dolonts 6-4, 6-3 in the first round. Williams was supposed to face 22nd-seeded Sabine Lisicki on Wednesday.
Williams had cited a virus when withdrawing from hard-court tuneup tournaments between Wimbledon and the U.S. Open.
"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."
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 having won seven Grand Slam singles titles, Williams was unseeded at the U.S. Open because her ranking 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 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.
After her victory Monday, Venus Williams was asked about the illness that caused her to skip tournaments this summer. She said that night she had been diagnosed, but wouldn't say with what.
"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."
AP National Writer Eddie Pells and AP Sports Writer Rachel Cohen in New York and AP Science Writer Alicia Chang in Los Angeles contributed to this report.