Bidding for a record-equalling sixth Roland Garros crown, an off-colour Nadal had to fight back from a one-set deficit to win 6-4, 6-7 (2-7), 6-7 (2-7), 6-2, 6-4 in a four hour, five minute thriller on Court Philippe Chatrier.
"Tres, tres difficile!" said Nadal in an on-court interview, after a victory he greeted by leaping off his feet and punching the air.
"He was a very, very tough opponent. His serve is almost unstoppable at times, so I just want to congratulate him for this fantastic match.
"It's important to go through these difficult moments. I would prefer to win in three sets but I'm trying to be positive so maybe that can help me in the future."
Nadal went through last year's tournament without dropping a set and had never lost a set in the Roland Garros first round, but he found himself 2-1 behind after being undone by Isner's booming serve in consecutive tie-breaks.
Isner took a 5-2 lead in the first tie-break and when a wayward return from Nadal gifted the American four set points, Isner grabbed the opportunity to level the match with a lusty serve that left the champion floundering.
The 24-year-old was not patrolling the clay with anything like his usual authority and two spurned set points in the third set allowed Isner to drag him into another tie-break.
Once again, Isner assembled a 5-2 lead and when Nadal needlessly netted a backhand the American pounced, slamming home a forehand return to take the set.
Isner proved his stamina by outlasting France's Nicolas Mahut in a world record 11 hour and five minutes marathon at Wimbledon last year, but Nadal closed the door on an upset by asserting control of the fourth set.
With a packed central court scenting an upset, Nadal dug deep to level the match and then procured the single break of serve he needed in the decider to take his place in the second round where he faces Pablo Andujar.
British fourth seed Andy Murray comfortably moved into the second round by dispatching stylish French qualifier Eric Prodon 6-4, 6-1, 6-3 on Court Suzanne Lenglen.
He will play Italy's Simone Bolelli for a place in the last 32.
"It was a tough match," said Murray, whose best Roland Garros performance was a quarter-final showing two years ago.
"There was no rhythm to the match at all. He didn't want to have long rallies so he hit a lot of drop shots and changed the pace of the ball."
Fifth seed Robin Soderling, runner-up for the last two years, overcame a second-set wobble to defeat American lucky loser Ryan Harrison 6-1, 6-7 (5-7), 6-3, 7-5 and set up an encounter with Albert Ramos-Vinolas of Spain.
Austrian eighth seed Jurgen Melzer, a losing semi-finalist last year, beat Germany lucky loser Andreas Beck 6-3, 6-4, 6-2, but there was a shock defeat for 11th-seeded claycourt specialist Nicolas Almagro of Spain.
Almagro has won three claycourt titles this year and reached the Roland Garros quarter-finals on two occasions, but he came a cropper in a 3-6, 2-6, 7-6 (7-3), 7-6 (7-5), 6-4 defeat by Polish qualifier Lukasz Kubot.
"He's a very aggressive player and he hit the ball well today," Almagro said.
"I started the match well, won the first two sets but then lost the tie-break. I served for the match in the fourth set. Nothing to do.
"He was better than me and in the end, he beat me."
Kubot, who had never won at the French Open before, prevailed in three hours and 50 minutes and will now meet Carlos Berlocq of Argentina.
Rising Ukrainian star Oleksandr Dolgopolov, the 21st seed, 20th-seeded German Florian Mayer and America's Sam Querrey, the number 24 seed, also came through their first-round ties.
- AFPTags: sport, tennis, france First posted May 25, 2011 06:00:00