Safina led by a break in the final set but could not close out the match
World number one Dinara Safina was dumped out of the LA Championships by China's Zheng Jie.
The Russian was beaten 7-5 4-6 6-4 by the 14th seed, who booked her place in the quarter-finals with the win.
Fifth seed Nadia Petrova also went out to Flavia Pennetta as sixth seed Ana Ivanovic lost to Samantha Stosur.
But Maria Sharapova saw off Alona Bondarenko 4-6 6-0 6-3, while second seed Vera Zvonareva beat Yanina Wickmayer 7-6 (7-5) 4-6 6-4.
Eighth seed Agnieszka Radwanska also avoided an upset as she eased to a 6-3 6-2 win over Anna Chakvetadze.
It's tough to play her but I didn't do the right things
Radwanska's sister Urszula progressed to the last eight with a walkover because of Chinese 12th seed Li Na's right knee injury.
Romania's Sorana Cirstea completed the quarter-final line-up as she was 6-3 1-0 up against Sabine Lisicki when the 17th-seeded German retired with an injury to her right shoulder.
Safina had appeared on course for victory at 4-2 in the third set against Zheng but she imploded completely, handing back the break with a double fault before losing the final eight points of the match.
"It's tough to play her but I didn't do the right things," said the Russian. "I should have played better. She took her chances and beat me."
Zheng said: "I know she has the big serve, but her moving is not so well. I tried to give her more forehands and get her moving more.
"I just want to enjoy it tonight and have some good sleeping."