Stefanos Tsitsipas tumbled out of the US Open against inspired Russian Andrey Rublev.
Tsitsipas, seeded eight at Flushing Meadow, has now endured consecutive first-round exits at grand slams following his early departure from Wimbledon.
The 21-year-old was clearly struggling with cramp during a ding-dong encounter on Louis Armstrong.
Yet he put in a serious fight, breaking Rublev to love as he served for the match.
But Rublev, also 21, was not to be denied and broke straight back before holding his nerve and his serve to wrap up a breathless 6-4 6-7 (5) 7-6 (9) 7-5 win.
World number 43 Rublev, who beat Roger Federer in Cincinnati earlier this month, said: "It was tough conditions for both of us and we played an amazing match.
"He started to cramp, I know what it's like, I was cramping too and tried not to show it. But this is amazing, winning matches like this gives you confidence."