The men's defending champion, Spaniard Juan Carlos Ferrero, struggling with a stomach strain, bruised ribs and a wrist injury, lost 6-4, 6-2, 6-3 to unseeded Russian Igor Andreev.
Andreev, who once did fitness training with Ferrero two years ago and had never won a grand slam match before this tournament, took full advantage of the beleaguered Spaniard at one stage, to win 17 points in a row.
Earlier, Venus Williams, the fourth seed and champion at Roland Garros in 2002, beat unseeded Jelena Kostanic of Croatia 6-3, 6-3.
The American, who won here in 2002, lost the first three games but improved to w in one hour, 21 minutes and she now takes on the 2000 French Open champion, Mary Pierce of France, for a place in the last 16.
The men's top seed Roger Federer of Switzerland beat the unseeded German Nicolas Kiefer in straight sets.
A blistering forehand down the line on just the second point of the match helped the Swiss top seed to break Kiefer's serve in the opening game and he went on to take the first set 6-3.
That set the tone as the Wimbledon and Australian Open champion, who was beaten in the first round here in 2002 and 2003, defeated his opponent 6-3, 6-4, 7-6 (8-6) in two hours and 31 minutes and he will now face three-time French Open champion Gustavo Kuerten of Brazil, seeded 28 this year, in round three.
After struggling in her opening game, Jennifer Capriati improved significantly as the ladies seventh seed brushed aside Czech qualifier Kveta Peschke 7-5, 6-3.
The 2001 Roland Garros champion, was taken to three sets in her first round win over Ukraine's Yulia Beygelzimer but the 28-year-old dominated her second game on the red clay and wrapped up victory in just 73 minutes.
She will now face either Anna-Lena Groenefeld of Germany or Australia's Samantha Stosur in round three. (AP)