Rafael Nadal suffered a shock exit from the Cincinnati Masters at the hands of 19-year-old Czech Tomas Berdych.
Nadal's 16-match unbeaten streak ended as he looked tired against a determined opponent who saved three match points in a 6-7 (4-7) 6-2 7-6 (7-3) win.
The Spanish teenager twice required on-court treatment for back problems in the pulsating three-hour marathon.
Australian Open champion Marat Safin and beaten finalist Lleyton Hewitt both came through straight-set wins.
World number two Nadal found fellow 19-year-old Berdych more than a match in a pulsating contest.
Nadal snatched the first set 7-4 in a tie-break but world number 36 Berdych took the second with punishing groundstrokes that the mobile Nadal could not hunt down in his 74th match of the year.
Berdych looked poised for victory when he broke to lead 5-4 in the third set.
But Nadal broke back and held three match points, only for Berdych to save them all and force a tiebreak.
A double-fault from Nadal gave Berdych three match points, and he clinched victory on the first.
Safin won his first match since Wimbledon on Tuesday, beating Jan Hernych 7-6 (7-3) 6-4 in the second round of the Cincinnati Masters.
The Russian had been struggling with a knee injury after losing to Feliciano Lopez at SW19.
Lleyton Hewitt, who retired in his opening match at last week's Montreal Masters with a stomach upset, beat Igor Andreev 6-3 6-4.
Elsewhere, Robby Ginepri surprised 10th seed Mariano Puerta 7-6 (7-2) 6-1.
Dominik Hrbaty beat Thomas Johansson, seeded 13, 6-1 7-5, and Paul-Henri Mathieu edged Tommy Haas 6-3 2-6 6-1.
Sixth seed Nikolay Davydenko saw off Sebastien Grosjean 7-6 (7-4) 7-5.