Top seed Ana Ivanovic was stunned at the US Open as she was defeated 6-3 4-6 6-3 by Julie Coin in the second round.
Ranked 188th in the word, Frenchwoman Coin recorded eight aces and benefited from 34 unforced errors by Ivanovic to bounce the Serb from the tournament.
Hampered by a thumb injury that kept her out of the Beijing Olympics, Ivanovic pulled out a 6-1 4-6 6-4 victory over Russian Vera Dushevina on Tuesday in the first round.
The 20-year-old Ivanovic is one of three women - along with Jelena Jankovic and Maria Sharapova - to hold the top spot in the rankings since last year's US Open winner, Justine Henin, retired in May.
Serena Williams breezed into the third round after defeating Elena Vesnina of Russia 6-1 6-1 at Arthur Ashe Stadium.
No.4 seed Williams took just under one hour to see off her opponent, making just 13 unforced errors on the way to victory.
An eight-time Grand Slam singles champion, she ousted Ukraine's Kateryna Bondarenko 6-1 6-4 in the first round on Tuesday and joins her sister Venus in the next round after she had earlier defeated Paraguay's Rossana De Los Rios 6-0 6-3.
Venus later declared it was high time she added to her two singles titles at Flushing Meadows.
Williams has been the undisputed queen of Wimbledon in recent years, picking up her fifth grass court grand slam title and a second in a row in London earlier this year.
Yet the 28-year-old has not won her own national championship since going back-to-back in 2000 and 2001.
After demolishing Paraguayan qualifier De Los Rios in 59 minutes, the seventh seed agreed that her US Open success was by now a distant recollection.
"Oh, yes, I remember," Williams said. "I won't forget, but I'd like to have a more recent memory as of like '08."
"That's pretty much the goal. I guess, kind of overdue, got to win it to deserve it."
Williams said she was satisfied by her performance against De Los Rios, the 113th-ranked player in the world but that her rival had made life a little more difficult than the scoreline suggested.
"Well, yeah, pretty happy," she said. "I think I just had a lot more power than she did today. She plays a game where she hits a lot of high balls, which at my height (6ft 1in) doesn't, you know - I think it would be effective against a lot of players, but with my height and my reach, it doesn't faze me as much."
"I think that helped me."
"She kept raising the level of her game and making it more competitive, even in the end when I had the 40-love. So of course I didn't want to get back on serve, and it all went well with me."
Looking to win a second major of the year but with younger sister Serena seeded fourth and in her quarter of the draw, the injury-prone Williams said she was physically in as good a shape as she had been at Wimbledon, when she defeated her sibling in the final.
"I feel great. I love Wimbledon, obviously, but I still feel very confident," she added.
"Obviously winning Wimbledon makes you confident, so I don't have any complaints."
"Whichever way the draw goes, whichever way the matches go, as long as hopefully it's a win for me, I'm pretty happy about it."
"I'm