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Isner holds an impressive 8-3 record against Anderson, winning his last five meetings with the 32-year-old.
World number one Rafael Nadal set-up a mouthwatering Wimbledon semi-final against old rival Novak Djokovic after battling back to beat Juan Martin del Potro in a Centre Court thriller on Wednesday.
Nadal triumphed 7-5, 6-7 (7/9), 4-6, 6-4, 6-4 after four hours and 48 minutes to reach his sixth Wimbledon semi-final and 28th at the majors.
The two-time Wimbledon champion will face Djokovic, a three-time winner at the All England Club, for a place in Sunday's final.
Djokovic leads their epic head-to-head rivalry 26-25.
Isner enters first semifinals
John Isner will face Kevin Anderson in the Wimbledon semifinals after the American ninth seed won the battle of the big servers against Milos Raonic on Wednesday.
Isner's 6-7 (5/7), 7-6 (9/7), 6-4, 6-3 victory in the quarterfinals booked his first appearance in the last four at a Grand Slam.
On Friday, the 33-year-old will play South African eighth seed Anderson, who shocked defending champion Roger Federer in the quarter-finals earlier on Wednesday.
Isner holds an impressive 8-3 record against Anderson, winning his last five meetings with the 32-year-old.
Isner famously played in Wimbledon's longest ever match against Nicolas Mahut in 2010, but he had never been past the third round at the All England Club until this year.
That lack of success on the big stage wasn't just restricted to Wimbledon Isner had only made one Grand Slam quarter-final in his career, and that was seven years ago at the US Open.
But, in his 41st Grand Slam appearance, Isner is finally into the last four at a major.
The only man ever to make it to the semi-finals of a major after a longer wait is his compatriot Sam Querrey, who needed 42 attempts.
The last American man to reach the Wimbledon final was Andy Roddick in 2009 and the last to win the title was Peter Sampras in 2000.
In a battle of Wimbledon's leading serves -- they went into the match both having hit over 100 aces in their five matches -- it was Raonic who drew first blood as he chased a return to the final two years after losing to Andy Murray.
But the Canadian 13th seed couldn't maintain that momentum in front of a virtually deserted Court One as fans left to watch England's World Cup semi-final against Croatia.
Once Isner hit back to take the second set, Raonic seemed to lose heart and the towering American was soon celebrating the best win of his career.
