British number one Kyle Edmund lost 6-4 7-5 to Canadian Denis Shapovalov in the second round in Cincinnati.
Edmund, 23, had his serve broken in the final game of a tight first set and, after seeing off five previous match points, finally succumbed to lose in an hour and 53 minutes.
World number 16 Edmund will continue his US Open preparation at the Winston-Salem Open, which begins on Saturday.
His best Flushing Meadows campaign was a run to the last 16 in 2016.
World number two Roger Federer, who turned 37 last week, overcame Germany’s Peter Gojowczyk 6-4 6-4 and said the victory helped consign his Wimbledon quarter-final defeat by Kevin Anderson to history.
Federer, who plays a limited schedule to prolong his career, has not played since a loss that marked his earliest exit at the All England Club since 2013.
“It’s nice to have played so that my last match was not the Anderson match. You’ve kind of turned the page. It’s a good thing,” he said.
“The goal is now to recover from this match, take the positives with me. Of course the big goal is the US Open.”
The Swiss will play Argentina’s world number 50 Leonardo Mayer in the next round.
Australian world number 18 Nick Kyrgios had to send a tournament official to retrieve his shoes from the locker room after he forgot to bring them to the court for his first-round meeting with American qualifier Denis Kudla.
The 15th seed endured some nervy moments, producing a second-serve ace when match point down before eventually prevailing 6-7 (2-7) 7-5 7-6 (9-7).