Cincinnati - Seven-time champion and third seed Roger Federer was knocked out of the Cincinnati Masters by world number 70 Andrey Rublev in the third round on Thursday.
Rublev won 6-3, 6-4 and will face fellow Russian Daniil Medvedev, the ninth seed, for a place in the semi-finals.
Federer, 38, will now head into the US Open later this month with just two matches on hard courts under his belt.
Cincinnati was his first tournament since losing the Wimbledon final in July to Novak Djokovic.
Rublev, 21, took less than an hour to earn his second top-five win in a month after beating Dominic Thiem in Hamburg on his way to the final.
Results on Thursday at the WTA/ATP Cincinnati Masters (x-denotes seeding):
Novak Djokovic (SRB x1) bt Pablo Carreño-Busta (ESP) 6-3, 6-4
Lucas Pouille (FRA) bt Karen Khachanov (RUS x8) 6-7 (3/7), 6-4, 6-2
Andrey Rublev (RUS) bt Roger Federer (SUI x3) 6-3, 6-4
Daniil Medvedev (RUS x9) bt Jan-Lennard Struff (GER) 6-2, 6-1
Roberto Bautista Agut (ESP x11) bt Miomir Kecmanovic (SRB) 6-1, 6-2
Richard Gasquet (FRA) bt Diego Schwartzman (ARG) 7-6 (8/6), 6-3
Yoshihito Nishioka (JPN) bt Alex De Minaur (AUS) 7-5, 6-4
David Goffin (BEL x16) bt Adrian Mannarino (FRA) 7-6 (8/6), 6-2
Ashleigh Barty (AUS x1) bt Anett Kontaveit (EST) 4-6, 7-5, 7-5
Maria Sakkari (GRE) bt Aryna Sabalenka (BLR x9) 6-7 (4/7), 6-4, 6-4
Karolína Plíšková (CZE x3) bt Rebecca Peterson (SWE) 7-5, 6-4
Svetlana Kuznetsova (RUS) bt Sloane Stephens (USA x8) 6-1, 6-2
Venus Williams (USA) bt Donna Vekic (CRO) 2-6, 6-3, 6-3
Naomi Osaka (JPN x2) bt Hsieh Su-wei (TPE) 7-6 (7/3), 5-7, 6-2
Madison Keys (USA x16) bt Simona Halep (ROM x4) 6-1, 3-6, 7-5
Sofia Kenin (USA) bt Elina Svitolina (UKR x7) 6-3, 7-6 (7/3)