On the most crucial point of the match, Anderson recovered after a fall and hit a lefty forehand to go up 0-30 while Isner was serving at 24-24.
A showdown between two tennis skyscrapers - with Isner topping the 6 foot 8 Anderson by two inches - predictably featured three tiebreaks and 102 thunderbolt aces but it was the 32-year-old South African who delivered the knockout blow. Isner in particularly started to appear tired at the set wore on.
After taking a medical timeout after the third set, Anderson surprisingly broke Isner's serve at 2-all in the fourth. But the South African was broken right back and couldn't capitalize on two set points in the tiebreaker - double-faulting on the first.
At Wimbledon, there are no fifth-set tiebreaks, a rule with which Isner is extremely familiar, so one of the players was going to have to break the other's serve at least once in order to reach the final.
Because of the length of the first match, that semifinal will be played with the roof closed. Djokovic owns 12 Slam trophies, three from Wimbledon.
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Isner leads Kevin Anderson 6-7 (6), 7-6 (5), 7-6 (9) in their semifinal on Centre Court.
John Isner has won the second set against Kevin Anderson 7-6 (5) to level their Wimbledon semifinal at 1-1.
With a spot in the Wimbledon final on the line, the two power players beat each other to a standstill in a match that stretched nearly seven hours.
As the endless games piled on in the fifth set, fans on Twitter grew restless. Their rivalry is a unique one as it dates back to the college days.
The Canadian and partner Yifan Xu of China, seeded sixth, lost 6-3, 4-6, 7-5 to No. 12 seeds Nicole Melichar of the USA, and Kveta Peschke of the Czech Republic in the Wimbledon semifinals on Friday.