Madrid beat Barcelona 1-0 in Wednesday's Copa del Rey final and scored a late goal to earn a 1-1 draw when the teams met in the league last weekend.
Madrid coach Jose Mourinho appears to have gained the upper hand tactically over counterpart Pep Guardiola and was in charge of Inter Milan when the Italian team ground out a two-legged win over Barca in the semifinals of last season's competition.
"Few people are betting on us, but we will go for it," said Guardiola, whose side is eight points clear of Madrid in the Spanish league. "Now it's evident that Madrid is much better than we are." In the other semifinal, German side Schalke, the surprise package in the competition this campaign, hosts English leader Manchester United in the first leg on Tuesday.
"I know we are the favorites but that doesn't mean anything," United captain Nemanja Vidic said.
The meeting of the two Spanish powers at the Santiago Bernabeu will be their third in 12 days, with a fourth "clasico" to come in the second leg on May 3.
Barcelona, a three-time Champions League winner like United, has been most pundits' favorites for the title after the team's sensational form and attacking prowess this season but question marks are suddenly being asked of its durability.
Guardiola's pessimism may also stem from the fact that injury problems are hitting his side, especially in defense.
"If we only go looking for an acceptable result in the Bernabeu, they will roll over us," Guardiola said. "We have to go looking to score goals. We have two left backs out and a third that is a doubt.
"These are things that happen, but we are who we are. We are not in the best of shape, but we are excited for the game." Adriano and Eric Abidal are the left backs missing while Maxwell, who would usually fill in, had to be substituted with a lower body injury in the 2-0 win over Osasuna on Saturday. Center backs Carles Puyol and Gabriel Milito are doubts, meanwhile, leaving Gerard Pique and attacking right back Dani Alves as the team's only genuine defenders.
With key players such as Brazil playmaker Kaka and Argentina striker Gonzalo Higuain back fit after long-term injury, Mourinho suddenly has plenty of options throughout his squad.
The nine-time European champions backed up its Copa del Rey success with a 6-3 win at Valencia in the league on Saturday, secured with largely reserve-team players.
"A team that plays like that a few days after winning the Copa del Rey demonstrates that it wants to finish the season strong," said Kaka, who scored twice against Valencia.
Madrid has succeeded in slowing down Barcelona's attacking game with an ultra-defensive lineup and physical tactics.
The same can be expected on Wednesday.
Barcelona midfielder Sergio Busquets said Sunday that "Madrid is the worst opponent we could play now. They know us and we've played evenly balanced games with them.
"We have to play our football and apply our philosophy.
We have to play as we did in the second half at Mestalla when we deserved more. We have to improve if we want to win." Mourinho, who is looking to win the competition with a third different team after triumphing with FC Porto and Inter, will be without injured Germany midfielder Sami Khedira.
United is within touching distance of a record 19th English title, needing seven points from its last four matches to guarantee the championship.
Alex Ferguson's team will be expected to beat Schalke, which is languishing in midtable in the German league but has showed its pedigree in Europe by ousting reigning champion Inter 7-3 in the quarterfinals.
"Schalke scored five goals away from home against Inter," Vidic said. "You have to respect that. Any team you play at this stage of the competition is not going to be easy." Ferguson is a huge admirer of Raul and the former Spain striker, who has scored a record 71 goal in the Champions League and won it three times with Madrid, has been a key factor behind Schalke's march to the last four.
"We dream of beating United. Let's see if we're the better team," he told British newspaper The Guardian. "No one can believe this. A final would be even more incredible. I hope it's Madrid." Schalke coach Ralf Rangnick rested several starters in the 1-0 defeat at home to Kaiserslautern on Saturday _ his first loss since returning to the club.
Influential defender Benedikt Hoewedes missed the game through injury and is in a race against time to avoid joining Netherlands striker Klaas Jan Huntelaar on the sidelines.