Dominic Thiem and Kei Nishikori are the latest seeds to fall in Halle after they both suffered shock losses in the second round.
Nishikori, seeded seventh for the grass-court event in Germany, was beaten 6-2 6-2 by Russia's Karen Khachanov.
Third seed Thiem, who reached the French Open final against Rafael Nadal earlier this month, was stunned as he fell in straight sets to Japan's Yuichi Sugita 6-2 7-5.
The 24-year-old Austrian saved three match points on Sugita's serve but a long backhand on the fourth confirmed a place in the quarter-finals for the world No.52.
Khachanov will face Spanish fourth seed Roberto Bautista-Agut in the last eight after he eased past Dutchman Robin Haase 6-4 7-5.
"I had to play more aggressive," Khachanov said after recording his 20th match win of the season.
"I had good memories here on centre court. I played three matches here last year so it gave me a lot of confidence and experience. This year has been great so far."
After eliminating world No.18 Lucas Pouille on Monday, Greek teenager Stefanos Tsitsipas tasted a bitter defeat to American qualifier Denis Kudla.
Kudla sweeped up a 6-3 6-4 win for the right to face Sugita in the next round.
Defending champion Roger Federer is aiming for a record-extending 10th title in Halle and he will continue his campaign in the second round against Benoit Paire on Thursday.
Australia's Matthew Ebden will open proceedings against Germany's Philipp Kohlschreiber.
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