Top-ranked Nadal downed Spanish countryman Feliciano Lopez 6-4, 6-4 while second-ranked Federer eliminated ninth-seeded Juan Martin del Potro 6-3, 6-3.
In Saturday's semifinals, Nadal will meet the seemingly unsinkable Gilles Simon of France, while Federer will tackle fourth-seeded Andy Murray in a replay of the U.S. Open final.
Murray beat Gael Monfils of France 6-2, 6-2.
Simon outlasted Ivo Karlovic of Croatia 7-6 (1), 4-6, 7-6 (2).
Nadal and Federer have each won Madrid without playing the other. They have featured in four finals this year, with Nadal sweeping them all, including the French Open and Wimbledon.
Nadal, who had complained of a right leg injury at the start of the week, said he suffered shoulder pain against Richard Gasquet on Thursday and which continued into Friday, and he received mesotherapy treatment - microinjections into the hurting skin - just before playing Lopez.
"Right up to the last minute the doctors have been treating me for shoulder pain, I spent two hours with them before coming out on court,'' Nadal said.
Despite that concern, he was wary of Lopez, who ousted top-10 players David Ferrer and Stanislas Wawrinka. But he made the only break in the fifth game of the first set and ninth game of the second, helped by Lopez's 33 unforced errors.
"This surface favored Feliciano, he likes to play here and at this altitude,'' said Nadal. "So I think I've played a very serious match.''
Federer used an effective slice serve on the fast indoor surface against del Potro and was never broken.
"The slice goes nicely on this court, I felt good using it to counter Juan Martin's height,'' Federer said.
Del Potro served 12 aces, including 11 in the first set, but his four double-faults cost him.
"Roger generates pressure just by being in front of you,'' the Argentine said. "I double-faulted on my serve in each set to lose the match. Roger gave nothing away and I wasn't able to even take a set off him.
"He broke my rhythm all the time and took full advantage of his break points, which I wasn't able to do.''
Murray was broken by Monfils in the opening game, but the Scot broke straight back and twice more to take the first set. The second set followed a similar pattern.
"(Monfils) almost enjoys running too much and almost likes you to dictate play,'' Murray said. "Once he gets used to big matches we're going to be seeing a lot more of him.''
Murray lost to Federer in straight sets in his first Grand Slam final a month ago, but Federer was expecting a harder match.
"I'll have to come with a proper game plan,'' Federer said. "He played well against Monfils, so I'll have my hands full with him.''
Simon, who staved off match points against Igor Andreev and Robby Ginepri, withstood 27 aces from Karlovic and rallied from a break down in the third set.
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