Clay court specialist Fognini, who was 0-7 on hard courts coming into the U.S. Open, played magnificently from the third set on, picking Nadal apart with groundstroke angles and deft play at the net, where the Italian won 39 of 54 advances.
The final set produced spectacular rallies and winners that had the Arthur Ashe Stadium crowd on their feet up to the 1:26 AM finish as the combatants traded seven service breaks in a row from the third game of the fifth set before Fognini held to end the three hour 46-minute tilt.
"Something incredible that I did today," said the 32nd-ranked Fognini, who won two out of three clay court matches against Nadal this year.
The loss ended eighth-seeded Nadal's record streak of 10 years in a row with at least one grand slam singles title after the Spaniard fell in the quarters at the Australian and French Opens, and was ousted in the second round at Wimbledon.
It was Nadal's first grand slam loss after winning the first two sets of a match. The only previous such defeat in his career came 10 years ago in the Miami finals to Roger Federer.
"He played great. I'm not happy he played better than me, but that's what happened," said 14-times grand slam winner Nadal.

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