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The Spanish second seed, who was the 2005 champion when the event was played on indoor hardcourt, held Isner to a mere 11 aces on the clay of the Caja Magica on a chilly day with the roof closed in case of rain.
Nadal found one ace himself in the low-key contest which ended after just under 90 minutes, with the four-time Roland Garros winner breaking late in the first set and early in the second to cement his 12th consecutive clay victory of the season.
Nadal has already lifted titles at his first two clay tournaments in 2010 - the Masters 1000 events in Monte Carlo and Rome - as he builds up towards the French Open which gets underway on May 23.
The Spaniard also defeated Isner, a surprise finalist last weekend in Belgrade on clay against compatriot Sam Querrey, on cement at Indian Wells in March.
Thursday's win was his 28th of the season.
The possibility of a potential semifinal between Nadal and compatriot Fernando Verdasco evaporated earlier as the sixth-seed lost to Austrian Jurgen Melzer 7-5 6-3.
Verdasco was guilty of 41 unforced errors, losing serve six times.
In the WTA event, Australia's Samantha Stosur and China's Li Na stormed into the last eight.
Eighth seed Stosur stopped Swiss Patty Schnyder 7-6 (7/3) 6-2 while Li, the 13th seed, put out Alona Bondarenko of the Ukraine with a 6-3 6-4 win.
Stosur next faces a test against fourth seed Venus Williams, against whom she stands 0-3 from 2007 and 2008 meetings.
Li will play Israeli Shahar Peer, who defeated Spain's Arantxa Parra Santonja 7-5 6-2.
Stosur remains a huge force on the spring clay after winning 14 of her last 15 matches on the surface, taking the title last month at Charleston and playing the final in Stuttgart against Justine Henin.
The 26-year-old from the Gold Coast leads the WTA standings for clay wins in 2010 and will move up to a career-high seventh in the world rankings next Monday, just in time for the countdown to the French Open.
The 2009 Roland Garros semi-finalist will arrive in Paris as the highest-ranked Australian woman since Wendy Turnbull was classed fifth in February 1984.
"I've played well since Indian Wells (in March)," said Stosur, who was broken in the penultimate game by Schnyder, but immediately broke the Swiss back to claim victory.
"That form just translated over to the clay. I'm enjoying my tennis, it's just one of those things. Once you start winning it doesn't matter which surface it's on, it gives you confidence." Stosur said that she got better as the contest with Schnyder went on.
"It was even in the first set with no breaks. The key was to hold serve," she said.
"I was feeling very comfortable in the second set. Schnyder is a tricky lefty who likes to hit a loopy ball and play the angles. My strategy was not to give her too many chances. "I'm feeling really good on the court and of course the confidence is growing." Li took 90 minutes to go past the 26th-ranked Bondarenko, who now trails the Chinese 1-3 in their head-to-head series.
