Champions Barca lead the standings after 16 games but are locked on 35 points with second-placed Real ahead of the eagerly anticipated match at the Camp Nou, known as "El Clasico".
The Catalan city is far calmer than in the aftermath of long jail sentencing to nine separatist leaders in October which unleashed waves of sometimes violent protests and saw the Oct. 26 game called off at the request of the league's organising body over security concerns.
But secretive Catalan protest group Democratic Tsunami has called supporters of the northeastern region's independence to gather in several areas surrounding the stadium four hours ahead of the game's kickoff.
The group, which organised mass protests at Barcelona's airport in October and blocked a major highway, said on its social media accounts that more than 25,000 people have confirmed they would take part in Wednesday's protests.
It said it does not wish to blockade or suspend the match, though, stressing that the protests are part of its effort to call for dialogue between Spanish and Catalan authorities on the region's independence drive.
Authorities have assembled a 3,000-strong force of public and private security officers to guarantee the match will not be disrupted, but declined to say how that compared to other "El Clasico" games.
Barca president Josep Maria Bartomeu said the club, which had condemned the jailing of separatist leaders, will make no effort to quell dissenting voices but added he was certain the game would go ahead without major incident.
"Whoever wants to protest peacefully can do so, the Camp Nou is a space for freedom of expression," he told reporters. "The game will not be postponed again, it's everyone's responsibility to ensure it goes ahead."
Former Real and Barca striker Alfonso Perez added: "There is a big security issue but it doesn't change the fact it's a huge match that millions will watch. It has to be played by any means possible, for the good of everyone."
Real goalkeeper Thibaut Courtois, meanwhile, was not concerned about his side's safety.
"We're only focusing on football," the Belgian said after Sunday's 1-1 draw at Valencia. "We're not worried about security, we wouldn't be travelling to the match if it wasn't safe."
Democratic Tsunami also said it has given instructions to supporters inside the stadium for yet unspecified actions.
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