Second seed Rafael Nadal's tour return ended prematurely after going down to Borna Coric in almost three hours in a pulsating second-round clash at the Western & Southern Open on Wednesday.
Coric, who underwent shoulder surgery in March, triumphed over the 22-time Grand Slam winner, 7-6 (11-9) 4-6 6-3.
The win was the Croatian's biggest of the season but it is a blow for Nadal's preparation for this month's US Open.
The Spaniard had pulled out of last week's Canadian Open in Montreal due to an ongoing abdominal issue, which he aggravated at Wimbledon, leading to his semi-final withdrawal against Nick Kyrgios.
Wednesday's meeting with Coric was Nadal's first match back, but the second seed had seven double faults and only managed 22 winners compared to the Croatian's 39.
Nadal had led 5-4 on serve in the first set before a one-hour rain delay, with Coric winning the tiebreak where both players had set points.
The 36-year-old converted the only break point in the second set to square the match up, but Coric broke to move 4-2 ahead in the deciding frame before finishing the job.
In-form Nick Kyrgios' run in Cincinnati was halted by 11th seed Taylor Fritz who triumphed 6-3 6-2 in just 50 minutes. Kyrgios committed 15-8 unforced errors along with six double faults, with Fritz firing down 16-7 aces.
Fifth seed Casper Ruud was bundled out 6-3 6-3 by American 19-year-old wild card Ben Shelton to secure his first-ever top-10 win. Shelton dropped just eight points on serve all match.
Eighth seed Hubert Hurkacz was also eliminated, going down 7-6 (7-5) 6-7 (5-7) 6-2 to big-serving John Isner. There were 32 aces in the 152-minute encounter, with Isner sending down 18.
Third seed Stefanos Tsitsipas cruised past Filip Krajinovic 6-3 6-4 in one hour and nine minutes to set up a third-round meeting with Diego Schwartzman. Tsitsipas blasted 28-16 winners.
Ninth seed Cameron Norrie came from behind to get the better of British compatriot Andy Murray 3-6 6-3 6-4 in a taxing encounter across two hours and 38 minutes. Norrie will next face Shelton.
Sixth seed Andrey Rublev overcame Fabio Fognini 6-7 (7-9) 7-6 (7-3) 6-2 and Denis Shapovalov beat Tommy Paul 3-6 6-4 6-3.
Jannik Sinner defeated Miomir Kecmanovic 7-5 3-1 in a walkover, with the Italian 10th seed to next meet Felix Auger-Aliassime who was too good for Alex de Minaur 6-3 6-2.
Spaniard Roberto Bautista Agut knocked off Marcos Giron 6-3 6-3, while Sebastian Korda rallied back to beat countryman Frances Tiafoe 4-6 6-1 6-4.