The Australian Open champion, who took over the No. 1 ranking by winning in Melbourne, came back to beat Alberta Brianti of Italy 6-7 (6), 6-4, 6-2 Monday.
Brianti, a 32-year-old veteran who has won one WTA title in her career, won the first set and then led 4-0 in the second before losing six straight games.
Although Azarenka won 12 of the last 14 games, she struggled with her game throughout, committing 60 unforced errors.
Azarenka started the 2012 season with a 26-match winning streak. Her first loss came in the quarterfinals of the Sony Ericsson Open.
She is now 36-3.
THIS IS A BREAKING NEWS UPDATE. Check back soon for further information. AP's earlier story is below.
Just playing at this year's French Open was an accomplishment for Venus Williams. Winning was a bonus.
Williams played at a major tournament for the first time since last August, when she withdrew before her second-round match at the U.S. Open. It was then that she revealed that she had been diagnosed with Sjogren's syndrome, a condition that can cause fatigue and joint pain.
It didn't slow her down in the last two sets Sunday. The seven-time Grand Slam champion recovered from a poor start and beat 19-year-old Paula Ormaechea of Argentina 4-6, 6-1, 6-3 to reach the second round.
"I just learned how to live with this. It's different. I have a lot to learn still," Williams said. "I learned how to just — just learning. So I think that's my biggest challenge. I learn a lot every week, especially having to play a professional sport.
"So that's a challenge, just learning to live."
Williams was one of six major champions that advanced on the opening day of the clay-court tournament. The only one that lost was Andy Roddick, the 2003 U.S. Open winner.
On Monday, top-ranked Novak Djokovic and 16-time Grand Slam champion Roger Federer will be on court. In the women's draw, No. 1 Victoria Azarenka and defending champion Li Na are scheduled to play.
Williams was last up in the main stadium, Court Philippe Chatrier, and she didn't get off to a good start.
Although Williams is the one with the fast serve and the pounding groundstrokes, it was Ormaechea that was on the offensive. The strategy worked, for a while.
"She played super well the first set," Williams said. "I think she really did a lot of the right things, and I have to congratulate her on the first set, and thankfully the next two sets were better for me."
Still, Williams had trouble on her serve in the final set, getting broken twice while winning four times on Ormaechea's serve.
"I wasn't able to get a foothold," Williams said. "She had some good returns. And so I had to give those to her, but I felt like I was returning well finally in the third."
U.S. Open champion Sam Stosur and former French Open winners Svetlana Kuznetsova and Ana Ivanovic also advanced to the second round.
The sixth-seeded Stosur, who lost in the 2010 French Open final, was first up on Court Philippe Chatrier. She beat Elena Baltacha of Britain 6-4, 6-0.
"It's a bit of an early start, but always nice to get through it now," the Australian said. "You have the whole day and whatever else to recover and, yeah, enjoy."
Kuznetsova won the French Open title in 2009 and the U.S. Open in 2004 but is seeded No. 26 this year. She defeated Mirjana Lucic of Croatia 6-1, 6-3. Ivanovic, the 2008 champion at Roland Garros, beat Lara Arruabarrena-Vecino of Spain 6-1, 6-1.
For the men, 2009 U.S. Open champion Juan Martin del Potro beat Albert Montanes 6-2, 6-7 (5), 6-2, 6-1. The ninth-seeded Argentine played with tape on his knee early in the match, and then added a wrap after a massage from a trainer following the second set.
"It's a problem when you can't find your balance like you're used to, but I'll use these few days of rest to get better," Del Potro said. "If I go on the court, it's because I feel good. I want to continue playing."
Juan Carlos Ferrero, the 2003 French Open champion, beat Jonathan Dasnieres de Veigy of France 6-1, 6-4, 6-3. The 32-year-old Spaniard is one of 37 men in this year's draw that is 30 or older, an Open era record for Grand Slam tournaments.
"I saw myself in the mirror, and when I walk on the court I don't think about whether I'm younger or older. The only thing I try to do is play well," Ferrero said. "And I'm at Roland Garros, and the idea is to play well today."
Jo-Wilfried Tsonga, the highest-seeded player in action on Sunday at No. 5, also advanced. The Frenchman defeated Andrey Kuznetsov of Russia 1-6, 6-3, 6-2, 6-4.
After Tsonga wrapped up his victory, it was time for Williams to get on court. And although she made it through to the next round, many are still wondering how long her game can last.
"Oh, I already know I can play. That's not a doubt," Williams said. "Everything else is up in the air."