Defending champion Roger Federer became the second high-profile casualty at the Madrid Open when he was beaten 6-4, 1-6, 6-2 by Japanese 14th seed Kei Nishikori in the third round on Thursday.
The Swiss second seed's surprise reverse follows Tuesday's shock defeat for world number one Novak Djokovic to unseeded Bulgarian Grigor Dimitrov.
Federer, 31, was playing his first tournament since taking a break following his loss against Rafa Nadal at the Indian Wells Masters in March.
It was the 23-year-old Nishikori's biggest win since he beat Serb Djokovic in the semi-finals in Basel in 2011.
Federer’s defeat snapped the possibility of a semifinal with Rafa Nadal who earlier thumped unseeded Russian Mikhail Youzhny 6-2, 6-3 to claim a spot in the last eight.
The Spanish world number five fell in the third round of the clay Masters event last year but never looked under pressure against Youzhny and showed his recent seven-month injury layoff had not robbed him of any agility.
In other third round matches, Tomas Berdych of Czech Republic beat Kevin Anderson of South Africa 7-6(5) 7-5 and Pablo Andujar of Spain got past compatriot Daniel Gimeno-Traver when the latter retired at 5-5 in the first set.
Serena, Sharapova win
In the women’s event, a laid-back Serena Williams breezed into the quarterfinals with a 6-3, 6-1 drubbing of Maria Kirilenko.
The world number one and top seed, defending champion at the premier clay event in the Spanish capital, needed just over an hour to dismiss the 13th-seeded Russian and set up a last-eight meeting with Spanish wildcard Anabel Medina Garrigues.
Williams, chasing a fourth title of the year and the 50th of her career, was joined in the quarterfinals by second seed Maria Sharapova who knocked out unseeded German Sabine Lisicki 6-2, 7-5.
The Russian world number two and French Open champion will play Slovakian wildcard Daniela Hantuchova or Estonian Kaia Kanepi for a place in the last four.
Sania-Bethanie exit
Sania Mirza and Bethanie Mattek-Sands made an early exit in the doubles after losing their second-round match 5-7, 1-6 to Anastasia Pavlyuchenkova and Lucie Safarova.