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He won 6-3 4-6 6-4 6-0 to reach the French Open semifinals.
Nadal had beaten Schwartzman twice before at Roland Garros, but he seemed to have met his match as the Argentine played with confidence, dominating the longer rallies and for a brief moment it seemed he had exposed a chink in the Spaniard's armour.
Dominic Thiem was the last player to take a set off Nadal in the 2019 final but Schwartzman ended the 13-time winner's run of 36 consecutive sets at Roland Garros.
"Losing sets is something I accepted during my tennis career. The thing that matters is how you recover from a set lost," Nadal, who is chasing a record-extending 21st Grand Slam title, told reporters.
Nadal stormed back into the match with a vengeance, wrapping up the final set in 26 minutes to move into his 14th Roland Garros semifinal where he will play either top seed Novak Djokovic or Matteo Berrettini.
Early in the opening set, Schwartzman was forced to save two break points, one electric rally ending when he won the point with a controlled lob over Nadal that earned the Spaniard's applause.
Nadal broke to love on Schwartzman's next service game with three consecutive winners to put pressure on the 28-year-old 10th seed, who broke back with a sharp forehand winner.
A second consecutive service break gave Nadal a 5-4 lead and this time he made no mistake on serve, closing out the set with a forehand winner down the line.
A fired-up Schwartzman raced into a 3-0 lead in the second set on the back of long rallies and clever approach shots to close out points which forced Nadal to go on the defensive.
Nadal won 12 of the next 14 points to level at 3-3 but an unfazed Schwartzman found a higher gear to hold serve, taking a 5-4 lead before breaking to level the match as the Philippe Chatrier crowd roared its approval.
The third set went with serve as both men played their attacking shots with precision.
But Schwartzman cracked at 4-4 and two loose shots allowed Nadal to take control and he converted a break point to go 5-4 up before he served out to love to lead two sets to one.
"At 4-4 [in the third], returning with the wind helped," Nadal said.
"If I played a bad game there, I would have been in a tricky situation, saving (the game) to not lose the set. He's a great player... I needed to play a little more aggressive and I think I did."
By the fourth set a tired Schwartzman was reduced to little more than a bystander, angrily talking to himself between points as his unforced errors count mounted as Nadal sent winners whizzing past him.
"At the end it was very difficult. I had the chances today, maybe in the third [set]. I was close," Schwartzman added.
"I was playing a little bit better than him. At the end, he's Rafa and he's always finding the way."