Serena Williams enjoyed an excellent first day at the US Open without even hitting a ball as five seeds in the American's half of the draw lost in the first round.
Seventh seed Ana Ivanovic led the list of challengers to fall at the first hurdle but there were also surprise defeats for eighth seed Karolina Pliskova, 10th seed Carla Suarez Navarro, 21st seed Jelena Jankovic and 30th seed Svetlana Kuznetsova.
Third seed Maria Sharapova, due to meet Williams in the semi-finals, also withdrew on Sunday due to injury.
The exits in theory should ease the American's path to the final as she bids to become the first female player in 27 years to win a calendar grand slam.
Ivanovic, who beat Williams in the 2014 Australian Open, was playing the opening match of the tournament in Arthur Ashe Stadium and the home crowd were not made to wait long for an upset as she lost 6-3 3-6 6-3 to Slovakian Dominika Cibulkova.
Cibulkova represented a tough opening test for Ivanovic, having reached the Australian Open final only last year before falling down the rankings due to an Achilles injury.
It is the third time this season Ivanovic has been knocked out before the third round at a grand slam.
"It was a very tough match-up I thought, especially for the first round," Ivanovic said.
"I really felt like I had been improving. Last week I saw a huge improvement in my game overall - my serve was really good today.
"That's why it's so disappointing because it was a very tough first match I think for both of us.
"So it's not easy but today I felt like she used her opportunities better than I did."
Pliskova lost to American qualifier Anna Tatishvili, Suarez Navarro was beaten by Czech Denisa Allertova, while Jankovic and Kuznetsova fell to French duo Oceane Dodin and Kristina Mladenovic respectively.
Serena's sister Venus came close to joining the list of casualties but the 13-time grand slam champion dug deep to beat Monica Puig 6-4 6-7 (7/9) 6-3.
Venus will now play fellow American Irina Falconi in the second round.
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