BERLIN World number one Justine Henin was dumped out of the German Open by Dinara Safina on Thursday, losing 5-7 6-3 6-1 in the third round.
The French Open champion's defeat by the Russian 13th seed meant she missed out on a highly-anticipated quarter-final clash with former world number one Serena Williams.
The American fifth seed thumped Polish 11th seed Agnieszka Radwanska 6-3 6-1.
Holder and second seed Ana Ivanovic struggled against Austria's Sybille Bammer before emerging a 7-5 4-6 6-4 winner in the Steffi Graf stadium.
Belgian Henin had comfortably won five previous meetings against the powerful Safina but the seven-times grand slam champion was broken eight times on Thursday and looked well short of her best.
The 22-year-old Russian served for the match at 5-0 in the deciding set but the top seed saved three match points and broke back only to lose her service and the match in the next game when she skewed a backhand into the sidelines.
"It's never easy to lose and to lose that way," Henin said at a news conference.
"During the whole match I didn't have the intensity and the consistency and it was quite tough. There's nothing more I can really say. She's been better. That's it."
Moscow-born Safina said it was the best win of her career.
"Going into the match I had inside the feeling that today I have a chance," she said.
"Because for her it was the second match and I already played two matches so I was more into the tournament," she added after Henin got a bye in the first round.
"I just had to take my chances and not make the same mistakes against her I made in previous matches."
Henin, who owns four French Open titles, was playing a tournament on her favorite clay surface for the first time this year.
Looking to defend her title in Paris later this month, Henin said she would take a few days off before next week's event in Rome to recuperate.
Bammer beat Ivanovic on hard court at Indian Wells last year in their only previous meeting and the determined lefthander broke the world number two six times.
The Serb was forced on the defensive in the final set but converted her first match point with a thumping backhand drive down the line to close out the match in 2-1/2 hours.
Ivanovic next plays Hungarian 10th seed Agnes Szavay who beat France's Marion Bartoli, the eighth seed, 7-5 7-5.
Third seed Svetlana Kuznetsova of Russia was upset by 15th-seeded Ukrainian Alona Bondarenko, losing 1-6 6-2 6-2, while seventh seed Elena Dementieva beat fellow Russian Vera Dushevina 7-5 6-3.
Dementieva will next play Jelena Jankovic after the Serbian fourth seed overcame another Russian, Maria Kirilenko, 6-2 6-4.
(Editing by Ken Ferris and Pritha Sarkar)