Andy Murray was knocked out of the US Open by Fernando Verdasco, 5-7 6-2 4-6 4-6.
The Spaniard hit 52 winners in a match which lasted over three hours to secure only his second career win over the former World No.1.
In what was only his ninth match since returning from hip surgery, Murray went toe-to-toe with the 31st seed in blisteringly hot conditions during the second round in New York, before succumbing 7-5 2-6 6-4 6-4.
There were signs of the old Murray in some of the defensive lobs he hoisted, the backhands he drilled into the corners and, in particular, the fire he showed in a fourth set he almost turned around. But there was also the now-familiar limp, too many double faults and an understandable lack of match tightness that meant it was Verdasco who came out on top for just the second time in their 15 meetings.
Murray knows it is still very early in his comeback and playing two tough best-of-five-set matches will stand him in good stead, but these are baby steps and his ranking remains outside 300. The 31-year-old remains optimistic he can get back to his best and arrive at grand slams with ambitions to win titles again, rather than simply a match or two, but he knows there are no guarantees.
Andy Murray waves goodbye to the US Open
Image credit: PA Sport
He said: “There’s for sure doubts because you just don’t know. When I got the injury, I was ranked number one in the world. Twelve months later, things completely changed.
You just don’t know exactly what’s round the corner. If things keep going smoothly, physically I continue to improve, I believe that I will get back to competing for the biggest competitions because there’s no reason why I couldn’t. But when you continue to build up and start playing more tournaments, you don’t know how you’re going to respond. Because of the path that I’ve been on the last year with the many, many ups and downs, trying to come back, it not quite working, then ending up having the surgery and stuff, I think it’s completely normal to have those doubts.
Stan Wawrinka fought hard to beat 20-year-old French qualifier Ugo Humbert to earn a 7-6 (5) 4-6 6-3 7-5 win on Wednesday and a spot in the US Open third round.
"My level is there. I'm playing really good tennis," said Wawrinka afterwards. "I'm 33 years old, first time after big surgery that I'm pushing myself that much, but in general, I think I did enough hard work to know and have confidence in my fitness.
"I think there is good chance that I'm playing better the next round than today, so I'm positive with that."
The Swiss, 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.
The unseeded Medvedev outwitted his 20-year-old Greek opponent in long, intense rallies in blistering conditions as the sun beat down on an outside court at Flushing Meadows.
The in-form Tsitsipas reached the Canadian Open final this month before losing to world number one Rafael Nadal, but said he had found it hard to recover from another punishing match on Monday against experienced Spaniard Tommy Robredo.
"I had no energy. But I managed somehow, you know, rehabilitate and get ready for the second-round match," Tsitsipas told reporters. "But it didn't feel the same."
He struggled in the humid weather as temperatures climbed above 30 degrees Celsius.
"You breathe this heat that's coming, the moisture that's in the air. So you feel like you're empty," Tsitsipas said. "You're not breathing out, breathing in, breathing out, so it feels really awkward to be playing like this."
Rafa Nadal  beat Vasek Pospisil 6-3, 6-4, 6-2
Fernando Verdasco beat Andy Murray 5-7, 6-2, 4-6, 4-6
Juan Martin Del Potro beat Denis Kudla 6-3, 6-1, 7-6
Nikoloz Basilashvili beat Jack Sock  4-6, 6-3, 6-2, 7-6
Dominic Thiem beat Steve Johnson 6-7, 6-3, 5-7, 6-4, 6-1
Kevin Anderson  beat Jeremy Chardy 6-2, 6-4, 6-4