Henin's French Open preparations suffered a blow in Berlin
World number one Justine Henin was sent crashing out of the German Open by Russia's Dinara Safina on Thursday.
The Belgian, playing only her second match following a month off with a knee injury, went down 5-7 6-3 6-1.
It was Henin's first defeat on clay since losing to Svetlana Kuznetsova in the Berlin semi-finals last year.
There was another shock as third seed Kuznetsova lost 1-6 6-2 6-2 to Alona Bondarenko, but Serena Williams beat Agnieszka Radwanska 6-3 6-1.
"I tell myself if I play well, I make it easier on myself," said Williams, who is chasing her fourth straight title. "I'm not tired, I've had a lot of time off and I am in top shape."
Second-seeded Ana Ivanovic won through 7-5 4-6 5-4 against Sybille Bammer, while Jelena Jankovic, the fourth seed, beat Martia Kirilenko 6-2 6-4 and seventh seed Elena Dementieva downed Vera Dushevina 7-5 6-3.
Henin's defeat means she misses out on a clash with Williams in the last eight.
I didn't have the intensity, she just played better then me
A three-times winner in Berlin and four-times French Open champion, Henin had been looking to kick-start her season on her favourite surface ahead of defending her Roland Garros title later this month.
But despite having won all five previous meetings against Safina, the top seed struggled desperately on serve and was broken eight times.
"It was pretty difficult out there and very frustrating, I am very disappointed," said Henin.
"I struggled during the whole match, I didn't have the intensity, she just played better then me."
She added: "This week was important, not only in terms of the French Open, but also in terms of getting some confidence back.
"I will take a few days off, focus on Rome and we will see what happens now in the next few weeks."
Safina never had taken a set off Henin in five previous meetings.
"Going into the match, I had a feeling I could win - she hasn't played well since the Australian Open," said Safina.