La Liga title at stake in opening clasico
The arch rivals clash in three competitions: in La Liga on Saturday, in the final of the King's Cup next Wednesday and in the Champions League semi-finals at Madrid's home the Bernabeu on March 27 and at the Nou Camp on May 3.
Saturday's league game at the Bernabeu is, in some ways, the least significant of the four as leaders Barca have an eight-point advantage over Real with seven matches left. Pep Guardiola's side could lose and still coast to a third consecutive league title.
However, Saturday's result will also be hugely significant in psychological terms for fans and players for the following three matches.
Since Guardiola took the helm in 2008, Barca have proven invincible in the "clasicos", chalking up five consecutive victories.
The last of those was a crushing 5-0 rout at the Nou Camp in November, which ended Jose Mourinho's unbeaten start as Real coach. Breaking that dismal run is surely crucial for the nine-time European champions.
Guardiola has already warned against complacency, urging his players to go for the win on Saturday to effectively wrap-up the league title.
"It's a unique opportunity to strike a decisive blow," he said after last weekend's win over Almeria.
Real appeared to view things slightly differently after beating Tottenham Hotspur 1-0 to make the last four of the Champions League on Wednesday.
"What happens in one game has no significance over what will happen in the next," Mourinho told reporters.
"There are people who think that whoever wins the first match will be in a better position for the second. My theory is very simple. You play the first and when it is finished you start thinking about the second."
Real's top scorer Cristiano Ronaldo, who has yet to find the net against Barca, added: "He who laughs last, laughs loudest, and I hope it will be Madrid."
Mourinho's squad seems to be in better shape for Saturday with strikers Karim Benzema and Gonzalo Higuain and playmaker Kaka all coming back from injury in time for the season run in.
The Portuguese has successfully rotated his squad over the last week, trying out different tactical variations in games, and has a number of options available to him.
The mauling his side received at the Nou Camp five months ago illustrated the danger of allowing Barca to dominate possession, so he could move away from his standard 4-2-3-1 line up to pack the midfield with a third 'holding' player this time.
Barca's smaller squad, on the other hand, has been hit by the long-term loss of defender Carles Puyol and Eric Abidal, to injury and to liver surgery respectively.
Gerard Pique and the little-used Gabriel Milito are his only recognised centre-backs though midfielder Sergio Busquets and Javier Mascherano have stepped in to cover of late, but they have not looked as secure in defence as they were earlier in the season.
Argentina's Mascherano is suspended for Saturday.
Striker Bojan Krkic picked up a knee injury last weekend which restricts Guardiola's choices up front where leader of the line David Villa has not scored in nine outings.
Fortunately for Guardiola, World Player of the Year Lionel Messi is in scintillating form.
He is the league's top scorer with 29 goals, one ahead of Ronaldo, and in scoring against Shakhtar Donetsk on Tuesday took his tally for the season in all competitions to 48, setting a new club record.