Andy Murray’s return to the US Open lasted just two rounds as the 2012 champion was eliminated by No. 31 seed Fernando Verdasco 7-5 2-6 6-4 6-4.
The Spaniard will face a second-straight past champion at Flushing Meadows when he meets third-seeded Juan Martin del Potro in the third round.
Murray missed last year’s tournament because of a hip injury and didn’t consider himself a contender this year because of his lack of preparation.
Verdasco won for just the second time in 15 career meetings with Murray, who had multiple chances to even the final game of a 64-minute final set before the left-hander finished it.
The 2009 champion beat American Denis Kudla 6-3 6-1 7-6 (7-4).
Stan Wawrinka fought off punishing heat and a youthful challenge from French qualifier Ugo Humbert to earn a 7-6 (7-5) 4-6 6-3 7-5 victory and a place in the third round.
With temperatures at Flushing Meadows once again nudging towards 38 Celsius on Wednesday, Wawrinka and Humbert battled for nearly three hours and 30 minutes in the shadeless oven that is the Grandstand Stadium court.
Wawrinka – the champion in 2016 but unable to defend his title last year after undergoing knee surgery – had his fitness put to the test by the 20-year-old Humbert playing in his first tour-level event.
The lefthander let the three-times grand slam-winning Swiss know he was in for a long and sweaty afternoon after the first set went to a tiebreak and he levelled the match by taking the second.
But Wawrinka lived up to reputation as a battler and grimly hung on to take the next two sets.
The 33-year-old, who upset eighth seed Grigor Dimitrov in the opening round, now faces 25th seed Milos Raonic after the big-hitting Canadian blasted past Frenchman Gilles Simon 6-3 6-4 6-4.
“I knew it was going to be a difficult match. He was a younger player, qualified,” Wawrinka said. “I’m really happy with the victory. It was really tough conditions.”
Russia’s unseeded Daniil Medvedev upset 15th seed Stefanos Tsitsipas 6-4 6-3 4-6 6-3.
The in-form Tsitsipas reached the Canadian Open final this month before losing to world No.1 Rafael Nadal.