Serena and Venus Williams could have met in the third round at Roland Garros, but, surprisingly, neither made it out of round two on Wednesday.
After Venus was eliminated by Slovakia's Anna Schmiedlova in three sets on Court Chatrier to start the second round, the top-seeded Serena was stunned by Spain's Garbine Muguruza.
Schmiedlova, in her second French Open and fifth Grand Slam event, pulled off a 2-6, 6-3, 6-4 victory over the 29th-seeded Venus for her first-ever win against a top-30 opponent.
The shocker then came about an hour later on Court Lenglen, as the 20-year- old Muguruza took full advantage of an uncharacteristically sloppy Serena in a 6-2, 6-2 triumph. Muguruza's best result in five previous Grand Slam events was a fourth-round loss to Agnieszka Radwanska at the Australian Open earlier this year.
"It's a dream come true," said Muguruza. "Since I was a child, I thought, Oh, I want to play against Serena on center court, and today was the day, and I think I did very good."
Serena struggled with her typically devastating serve.
"I don't think anything worked for me," Serena said. "It was one of those days. You can't be on every day, and, gosh, I hate to be off during a Grand Slam. It happens."
It wasn't Serena's earliest exit at Roland Garros. She was bounced in the first round two years ago by Frenchwoman Virginie Razzano, then rebounded by completely dominating her opponents last year en route to her second French title -- dropping just one set in seven matches.
Serena's loss continued the run of surprising outcomes over the last three days in the French capital. Men's third seed Stanislas Wawrinka was sent home in the first round on Monday and Li Na, the women's second seed and 2011 champion, was knocked out Tuesday.
Russian great Maria Sharapova avoided an upset by stifling Bulgarian Tsvetana Pironkova 7-5, 6-2.
The seventh-seeded former world No. 1 Sharapova is perhaps now the favorite to capture the 2014 French Open. She titled here two years ago to complete the career Grand Slam and lost to Serena in last year's marquee finale in southwest Paris.
Sharapova has lost only four clay court matches since 2012, with three of them coming at the hands of Serena. The other one came against fellow former No. 1 Ana Ivanovic in Rome two weeks ago.
Eighth-seeded German Angelique Kerber also avoided an upset Wednesday by tackling American Varvara Lepchenko 6-2, 7-5, while ninth-seeded Aussie Open runner-up Dominika Cibulkova of Slovakia raced past Austrian Tamira Paszek 6-3, 6-4.
Promising American teenager Taylor Townsend made her Grand Slam main draw debut a successful one by taking out 20th-seeded French favorite Alize Cornet 6-4, 4-6, 6-4. The 18-year-old blew a 4-1 lead in the second set and was up big, at 5-1 in the third, before blowing four match points and letting Cornet pull within 4-5 in the stanza. But Townsend hung to advance amid some light rain.
Meanwhile, Sweden's Johanna Larsson rallied for a surprising 5-7, 6-4, 6-2 victory over 12th-seeded Flavia Pennetta of Italy, 14th-seeded Spanish clay-courter Carla Suarez Navarro defeated Swiss Timea Bacsinszky 7-5, 1-6, 6-4 and German Mona Barthel upset injured 16th-seeded fellow countrywoman Sabine Lisicki 6-1, 3-0. The Wimbledon runner-up Lisicki was forced to retire with right wrist injury she suffered after taking a spill on court in the opening set against Barthel.
In other action involving seeds, No. 18 Canadian Eugenie Bouchard came back from a set down to post a 2-6, 6-2, 6-1 win over German Julia Goerges; No. 19 former U.S. Open champ Sam Stosur leveled Austrian Yvonne Meusburger 6-1, 6-3; No. 31 Slovakian veteran Daniela Hantuchova took care of France's Claire Feuerstein 6-1, 6-4; and Croat Ajla Tomljanovic upended No. 32 Russian Elena Vesnina 7-6 (8-6), 6-2. Bouchard captured her first-ever WTA title last week in Nuremberg, Germany. Stosur was a French Open runner-up back in 2010.