A first-half penalty from leading scorer David Villa, second-half headers from Argentine centre-back Roberto Ayala and substitute Mista and a late strike from Ruben Baraja earned Valencia their comfortable victory at the Mestalla.
A ragged-looking Real took the lead against a dominant Getafe thanks to a disputed strike from Brazilian forward Julio Baptista, but the home side grabbed a deserved point when defender Manuel Tena headed in seven minutes from time.
The results mean that Barcelona will have a chance of retaining their league title next week if they can win their match at Sevilla and Valencia slip up at Athletic Bilbao.
The Catalans went a step closer to the championship with a 1-0 victory over Villarreal on Friday, leading striker Samuel Eto'o notching his 24th goal of the season with his 11th-minute winner.
With five games left Barca have 73 points, 11 ahead of Valencia and 13 clear of Real
Fourth-placed Osasuna are a point behind Real after their 1-1 draw with basement side Malaga.
Valencia did not take the lead against Espanyol until late in the first half when Villa scored from the penalty spot after being brought down.
There was no way back for Espanyol once midfielder Eduardo Costa was sent off on the hour and Ayala made it 2-0 soon after when he nodded in a Villa free kick.
HALF VOLLEY
Unmarked forward Mista stopped low to head in the third on 70 minutes and Baraja wrapped it up when he cracked in on the half volley after a corner just before the final whistle.
Veteran Italian defender Amedeo Carboni had a marvellous game at the back for Valencia on his return to the starting line-up at the age of 41.
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Real Madrid coach Juan Ramon Lopez Caro decided to leave England captain David Beckham on the bench at the start against Getafe, preferring to play Brazilian wing back Cicinho on the right and Uruguayan Pablo Garcia in the middle.
His tactical tinkering had little effect, however, as Real gave a ragged display in the first half and would have trailed their neighbours had it not been for a string of sharp saves from Iker Casillas.
However, Real took the lead against the run of play when Baptista, who had hit the bar in the first half, steered in from the edge of the area on the hour, although Getafe protested strongly because the Brazilian had controlled the ball with his hand.
Getafe continued to have the better of the play, though, and gained a deserved equaliser when Tena outjumped the Real defence to send a glancing header past Casillas after Cosmin Contra had whipped in a free kick from the left.
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