Real are five points behind leaders Barcelona in the Spanish first division and will hope to continue their remarkable run over neighbours Atletico who have not won a derby match since 1999 and have already lost three times to Real this season.
Madrid will be full of confidence after their 3-0 home win over Lyon on Wednesday saw them reach the last eight of the Champions League for the first time since 2004 having fallen at the last 16 stage for six successive seasons.
"Those of us who have been in the team longer have tasted all those defeats, but we all knew Real Madrid had to be in the quarter finals," said captain Iker Casillas. "Now we have to change our mindset because we have two days to prepare for a very important game (against Atletico)."
Madrid beat Atletico 2-0 in the league at the Bernabeu and then won 1-0 and 3-1 in the two legs of the Kings Cup quarter-final so the omens don't look good for Atletico.
Real also have Cristiano Ronaldo back fit after the Portuguese star came through the Lyon match unscathed and Atletico will be aware of in-form Karim Benzema who has scored twice in each of his last three league matches.
Atletico lie down in eighth, three points off the top six, after a disappointing league campaign so ending the derby hoodoo would be a real highlight for the suffering fans.
"It is not normal to go so many years (without winning a derby) and our fans deserve a win over Real Madrid," Atletico goalkeeper David de Gea said. "We are not afraid of Real Madrid or (Jose) Mourinho."
Champions Barcelona dropped two points in a 1-1 draw at Sevilla last time out and hope to get back on track with a home win over Getafe on Saturday.
Barca hold a five point cushion over Real at the summit and will be keen to maintain that lead ahead of the second 'El Clasico' at the Santiago Bernabeu on the weekend April 16/17.
"We have to reach that game (against Real Madrid) with the maximum points possible," said Barcelona defender Gerard Pique. "We can do that by winning all the games before that date."
Barcelona have been rocked by the news that French defender Eric Abidal, 31, needed surgery to remove a tumour in his liver.
"He (Abidal) is a strong person, mentally one of the strongest I know," said midfielder Xavi.
Valencia host Sevilla on Sunday looking to put last weekend's 4-0 humiliation by Real Zaragoza to the back of their minds.
Valencia have wobbled of late with the Champions League last 16 exit to Schalke followed by the Zaragoza fiasco, however, the club are well-placed in third, three points ahead of Villarreal.
"We have to apologise to the fans for the terrible game (against Zaragoza)," said Valencia defender David Navarro. "There are no excuses and we are convinced that we can pick ourselves up and turn in a good performance against Sevilla."
Villarreal missed the chance to close in on Valencia last weekend and have a tough trip to face Athletic Bilbao on Sunday.
Bilbao lie sixth largely on the basis of their strong home form with ten wins from their 14 outings at San Mames.
At the bottom the three teams in the relegation zone, Malaga, Hercules and Almeria, are all level on 26 points.
Malaga prop up the table, despite winning at Real Sociedad last weekend, and have a tough match at home to fifth-placed Espanyol on Sunday.
Third from bottom Almeria travel to fellow strugglers Sporting Gijon, three points above them, on Sunday in a crucial six-pointer.
Hercules, the only team to beat Barcelona in the league this season, are the only promoted side in the bottom three and host Osasuna on Sunday.
Flying Real hope for more derby joy
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