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.
"It's a unique opportunity to strike a decisive blow," he said after last weekend's win over Almeria.
"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 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.
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