Blinking back tears and ignoring pain, American teenager Melanie Oudin defeated No. 4-ranked Elena Dementieva 5-7, 6-4, 6-3.
Then No. 5 Jelena Jankovic lost 6-3, 6-7 (4), 7-6 (6) to Yaroslava Shvedova of Kazakhstan in a 2 hour-40 minute match. Jankovic reached the final in 2008, but her head might not have been focused on the court on this day: Her grandmother died on Wednesday.
The losses by Dementieva and Jankovic mean half of the top 20 seeded women are out of the draw. No. 23 Sabine Lisicki of Germany also is gone, having left in tears as she was taken away in a wheelchair after injuring her ankle at the end of a 6-3, 3-6, 7-5 defeat against Anastasia Rodionova of Australia.
No. 1 Dinara Safina nearly joined the parade of surprising exits, turning in her second poor performance of the week before hanging on to edge 67th-ranked Kristina Barrois of Germany 6-7 (5), 6-2, 6-3.
"Another tough day in the office," said Safina, who double-faulted 15 times, including three in the tiebreaker. "There is no problem in the technique or nothing. Just in my head."
In other action, 10th-seed Fernando Verdasco eased past Florent Serra of France 6-3, 6-0, 6-3, and No. 20 Tommy Haas of Germany and Americans Jesse Witten and No. 22 Sam Querrey also advanced. French Open runner-up Robin Soderling advanced when his opponent, Marcel Granollers of France, quit during the third game with a back injury.
On the women's side, No. 9 Caroline Wozniacki of Denmark, No. 13 Nadia Petrova of Russia, No. 21 Zheng Jie of China and No. 24 Sorana Cirstea of Romania progressed. No. 19 Patty Schnyder, No. 30 Alona Bondarenko of Ukraine and No. 23 Sabine Lisicki lost, with Lisicki wickedly spraining her ankle on match point and needing a wheelchair to be helped off of Court 11.
Oudin, aged 17 and ranked 70th, played most of the third set with a heavy wrap on her left thigh, while cramps briefly reduced her to tears as she headed to the baseline to serve.
"First time playing on Arthur Ashe, I was beating No. 4 in the world, about to beat her," Oudin said.
"Just a little bit of everything. A lot of things were going through my mind."
The match ended with a loud shriek when she painted the backhand corner with her serve on her third match point.
She'll be back for her third-round match against either 29th-seeded Maria Sharapova or Christina McHale, a 17-year-old American just like her.
Dementieva, meanwhile, leaves Flushing Meadows with the more accomplished resume - 14 titles, 14 runner-up finishes, more than $12 million in career earnings - but still in search of her first Grand Slam title. She was the runner-up here in 2004.
After Thursday's loss, Dementieva said she was impressed with America's new break-out player.
"She was in the court, not afraid to play, playing very aggressively, really enjoying this atmosphere and the crowd support," Dementieva said. "It looks like she has a good future."
Shvedova closed out Jankovic in the third-set tiebreaker with an ace after setting up match point with an overhead slam to end a long rally.
At Armstrong Stadium, Safina won despite 38 unforced errors and 15 double-faults.
She is ranked first despite having never won a major and she did little in this match against the 67th-ranked player in the world to cool the debate about whether she really belongs there.
Safina, playing in a smaller venue for a Thursday matinee, needed 2 hours, 13 minutes, much of which looked like the 2 hour-25 minute display she put on in her three-set opener against Olivia Rogowska of Australia.
"When you are playing on the court and you're fighting, maybe in some stages you're not playing your best," Safina said. "But you're still here and the crowd is supporting you and that just gives you another edge."
The Williams sisters won their opening doubles 6-2, 6-2 over Julia Goerges of Germany and Arantxa Parra Santonja of Spain, answering the questions about whether Venus would play in that event because of her sore knee.
"I actually felt pretty good today," Venus said. "I'm going to definitely be in both events."
