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South African Kevin Anderson recovered from two sets down to win a quarterfinal cliffhanger 2-6 6-7(5) 7-5 6-4 13-11 on a tension-filled court one in London on Wednesday (local time).
The 36-year-old Swiss, not playing on centre court for the first time since 2015, displayed his usual panache as he strolled through the opening two sets to stretch his streak of consecutive sets won at Wimbledon to 34.
But after squandering a match point in the 10th game of the third set Federer's game frayed at the edges and an inspired Anderson powered back to claim victory in four hours and 14 minutes.
It was the biggest shock in a tournament already brimming with surprises, especially as Joahannesburg-born Anderson had not even won a set in their four previous meetings.
While top seed Federer was only at his scintillating best in the first set, nothing could be taken away from Anderson.
The 32-year-old, who reached last year's US Open final, will face John Isner in the semis.
"Down 2-0 I tried my best to keep fighting and was able to scrape through and by the end I thought I did a great job. I was in the flow of the match," eighth seed Anderson said.
"Beating Roger Federer at Wimbledon will be one I remember. As the match went on, I gave it my all. I'm very ecstatic."
It is the second time that 20-time Grand Slam champion Federer has lost at Wimbledon from two sets ahead, suffering the same fate against Jo-Wilfried Tsonga in the 2011 quarter-finals.
"It just wasn't one of my best days," Federer, who won the first set in 26 minutes, told reporters.
The Swiss refused to blame his surprise defeat on the decision to play the match on court one rather than his customary Centre Court stage at the All England Club.
"I don't think it really mattered, to be honest. I had my chances and blew them, so... That's my problem really, the 36-year-old said. "I had my chances and I blew it."
Federer had breezed into the quarter-finals and was imperious in the opening set.
Anderson, the first South African to reach the last eight since Wayne Ferreira in 1994, was steadfast though and did what no man had done at Wimbledon since last year's semi-final when he broke Federer's serve early in the second set.
It snapped an 85-match run of holds by the Swiss but he did not flinch, hitting back to take the set on a tiebreak.
Federer's match point arrived when Anderson served at 4-5 in the third but, with the South African looming at the net, he made a hash of an attempted backhand pass.
The escape energised Anderson and he broke in the next game with a bludgeoning backhand off a weak second serve and then battled back from 0-40 to seal the third with an ace.
Federer seemed rattled and his forehand began to look vulnerable and it was that stroke which allowed Anderson a decisive break of serve at 3-3 in the fourth.
Anderson had Federer down 0-30 twice on serve in the early stages of the decider but the top seed's survival instincts kicked in and with the advantage of serving first it seemed inevitable that his opponent would crack eventually.
Six times Anderson was required to hold serve to stay alive and each time he was equal to the task.
It was Federer who faltered at 11-11, double-faulting to hand Anderson a break point which he converted when the defending champion's weary forehand smacked the net.
There was still the small matter of holding serve but a 28th ace helped settle Anderson's nerves and be brought up match point with a massive forehand before completing a remarkable victory with a first serve that Federer could not handle.