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World number three Nadal, playing just his third tournament of the year, is gearing up for a tilt at a record-extending 14th French Open title.
By defeating the man who landed the Monte Carlo Masters title last week, Nadal showed he is moving through the gears on his favourite surface before heading to Paris.
He won 6-4 6-7 (6-8) 7-5 to maintain his 100 per cent record in finals at this tournament on home soil, but Tsitsipas was left to reflect on a missed opportunity after the 20-time grand slam champion fended off a championship point at 5-4 in the final set.
Nadal trailed 4-2 in the opening set as Tsitsipas signalled he was up for the challenge and brimming with confidence, but back came the 34-year-old to sweep up the next four games.
Tsitsipas broke first in the second set too, inching 2-1 in front, and the Greek looked every bit a warrior capable of living with the best for much of the contest.
It was a rout when these two met in the Barcelona final three years ago, Nadal dropping only three games, but here he needed to work far harder, in what was the 69th clay-court final of his stellar career.
Tsitsipas beat Nadal from two sets down in the Australian Open quarter-finals in February, so dropping the opener here was not cause for panic, but nor was gaining the early break in the second any reason to be confident he would be taking the match to a decider.
Nadal duly broke back but then let two championship points slip by in the 10th game, with Tsitsipas serving. A smash followed by a superb drop volley from Tsitsipas meant the match remained alive.
Tsitsipas could not convert 0-40 on Nadal's serve in the next game, but he won a thrilling tie-break to take the contest all the way.
There was not a solitary break point in the decider until Tsitsipas was a point away from claiming the title in the 10th game, but the King of Clay dug in to hold.
He rubbed salt in the wounds by securing the elusive break in the next game and dropped to the clay in delight after serving it out, ending a pulsating showdown that was finally settled in three hours and 38 minutes.