Former French Open champion Stan Wawrinka continued to struggle with form and fitness as he was dumped out in the first round by Guillermo Garcia-Lopez on Monday, a defeat which will send his world ranking plummeting, while Victoria Azarenka also suffered a shock exit.
Wawrinka, who lost to Rafael Nadal in last year's final and won the 2015 title, was beaten in a five-set thriller 6-2, 3-6, 4-6, 7-6 (7/5), 6-3 by the Spanish world number 67 on Court Suzanne Lenglen.
The 33-year-old has been plagued by a knee injury and arrived at Roland Garros having won just one match on clay in Geneva last week, his first event in three months.
The defeat means that the three-time Grand Slam champion will slip from 30th in the world to outside the top 250 after the tournament, having failed to defend the ranking points he gained in 2017.
There were worrying signs for his fans when he pulled up with the same left knee injury that has plagued him in recent months and called for a medical timeout after just six games.
The 23rd seed looked to be really struggling as he quickly dropped the first set, but found his rhythm from nowhere in the second, crunching two massive forehands to break for a 3-1 lead.
A fired-up Wawrinka duly levelled the match, having saved a break point in the seventh game thanks to some magnificent defending in a brutal rally under the Paris sunshine.
Wawrinka saved a break point to serve out the third set after breaking in the opening game, as 34-year-old Garcia-Lopez threw his racket to the ground in disgust.
The match looked to be all but over when Wawrinka broke in game five of the fourth set, but he became ragged and Garcia-Lopez forced a decider by edging a tie-break.
Wawrinka's form totally deserted him in the fifth set, and Garcia-Lopez comfortably wrapped up victory.
Former world number one Victoria Azarenka's return to Grand Slam tennis lasted just two sets as the Belarusian slumped to a 7-5, 7-5 loss to Katerina Siniakova.
Azarenka, who missed much of last season after being embroiled in a custody battle over her son, was broken to love in the 12th games of each set to be dumped out by the Czech world number 57.
The two-time Australian Open champion has now won just two matches at Roland Garros in the last five years.
Siniakova moves onto a second-round match with Ukraine's Kateryna Kozlova, who stunned defending champion Jelena Ostapenko on Sunday.
It was Azarenka's first Grand Slam match since losing to Simona Halep in the Wimbledon fourth round last July, but she still believes she can return to the top of the game.
"No doubt about it. Maybe not today, but no doubt about it," the now-world number 82 insisted.
Petra Kvitova also found life hard, but the two-time Wimbledon champion fought back from a set down to beat Paraguay's Veronica Cepede Royg 3-6, 6-1, 7-5 on Court Philippe Chatrier.
The 28-year-old Kvitova is one of the favourites to win a maiden Roland Garros title after winning four titles this season, including on clay in Prague and Madrid.
"I've won 12 matches straight on clay, but I'm still a long way from Rafa," she said in reference to Rafael Nadal's upcoming bid for an 11th men's singles crown.
Elsewhere, Argentinian Marco Trungelliti saw off Bernard Tomic 6-4, 5-7, 6-4, 6-4, just 11 hours after arriving in Paris after driving back from Barcelona to take a lucky loser's spot on Sunday night.
The world number 190 was a record eighth player that lost in qualifying to take a place in the main draw.
Women's 21st seed Naomi Osaka of Japan won 24 of the last 27 points in an impressive 6-2, 7-5 victory over Sofia Kenin, while last year's US Open runner-up Madison Keys beat fellow American Sachia Vickery 6-3, 6-3.