Trailing their great rivals by 11 points in the league, Real -- who last week won the Club World Cup -- cannot afford to slip up at home if they are to retain hopes of winning the Spanish league title.
FC Barcelona became a symbol of Catalan identity during the dictatorship of General Francisco Franco which ruled between 1939 and 1975, giving rise to the club's motto "Mes que un club" (More than a club). Real, meanwhile, were the club of the capital and widely regarded as representing the Spanish establishment.
Catalonia's dramatic bid for independence in October -- on Thursday Catalan pro-independence parties held their absolute majority
in snap regional elections -- increases already heightened tensions ahead of Saturday's match.
But how will this potent concoction of politics, sport and history impact those closest to the action? Here are the stories of those whose pulses quicken most for the spectacle one observer described to CNN as a "cattle prod to the senses."
The Player - 'Losing to Barca feels like falling into the bottom of a well'
Former Brazil international Savio played for Real Madrid from 1998 to 2003, making 105 appearance and scoring 16 goals.
I've played in a number of big matches in Brazil, in France, and other derbies in Spain -- Zaragoza versus Osasuna in Spain's Aragon region, Flamengo versus Vasco da Gama in Rio -- but none of these can compare to Real versus Barcelona.
Everything about this rivalry is different, it's the biggest derby in the world because of the quality of players on display, the greatness of both clubs, the history and, most importantly, the political rivalry -- Catalonia with the independence issue and Madrid being Spain's capital.
During the week before the match there's huge expectation. You know that it's a match which will be watched everywhere in the world.
As a player who came from Brazil, little by little I started to learn what El Clasico actually means to people.
Before joining Real I'd follow the game in Brazil, but when you're living it up close, you learn more about the league, the rivalry, the culture, and I really got to understand what El Clasico was about. We didn't need the Spanish players to explain to us what the match meant, we could see for ourselves.
My favorite El Clasico was one whih ended 2-2 in the Camp Nou in 1999.
It was very dramatic match. We had gone 1-0 up through Raul, but Barca had hit back and were leading 2-1 until Raul equalized in the 89th minute and did the "shushing" gesture to the Camp Nou crowd, putting his fingers to his lips, which everyone remembers. I assisted two of the goals and ... I cherish this game a lot.
When you're in the stadium, be it Camp Nou or Santiago Bernabeu, there's huge pressure. The atmosphere is one of celebration, but there's also tension and the dressing room after an El Clasico can either be one of extreme happiness or sadness.
If you win, everything is wonderful, that's why it's such a special game. But when you've lost against Barcelona it feels like you've lost a big title or a trophy. Aside from losing against a rival, you have to face all the criticism -- from the fans to the media -- it feels like you've fallen to the bottom of a well.
The Barca fan - 'I just want to win -- even if it means Messi scoring with his hand'
Catalan Pau Riera, 29, is a lifelong Barcelona fan who now lives in London.
I live El Clasicos as if they were finals, regardless of the position Barcelona is in the table.
It doesn't really matter how your team is performing during the season. This match stands alone and I just want Barca to beat Real, even if it's with an offside goal in the 94th minute, or Messi scoring with his hand.
For some people, El Clasico goes beyond football and they see it as the relationship between Spain and Catalonia. However, I prefer to keep it as it is -- a sports event.
The rivalry has actually normalized over the last few years. When Jose Mourinho was in charge of Real, from 2010 to 2013, it got to a point that both teams were hating each other badly and there was too much tension around it.
For me, the worst moment though was when Luis Figo switched teams in 2000. I was a kid when that happened and he was by far my favorite Barca player. It hurt me so much that I hated him and Madrid for years and years.
During the match, streets are empty as everyone is at the bar. Clasicos are probably the most social football matches because even if they broadcast the match on TV you prefer to gather with your friends and watch it at the local bar.
Family-wise my parents and sister don't especially follow football, but they usually do for El Clasico. My Dad enjoys a Real defeat more than a Barca win!
Before and during the match, I'm definitely more nervous than I'm an for any other match. I suffer every time Madrid has the possession of the ball.
I've always said that the day Barcelona and Madrid play the final of the Champions League I will probably not be able to watch -- it'd be too much for me.
When Barca lose to Real, I'm usually in a bad mood until I manage to stop thinking about it. I can't read any sports news for the next couple of days.
But beating Real is a great feeling of euphoria and satisfaction. When Barca beat Real 6-2 at the Bernabeu in 2009, the score was so unexpected it meant the celebrations were more explosive too.
Every time Barcelona scored my friends and I were jumping, shouting and hugging random people that were also celebrating. People were on the tables, glasses were crashing ... it was a proper mad celebration.
I'll probably be watching Saturday's match at a pub with a couple of friends from Barcelona. Clasicos in London are always a lottery because you never know if you'll be surrounded by Madrid supporters. It's fun to see their faces if you win -- but if they beat us you just want to disappear.
The Journalist - 'It's a brilliant test of your ability'
Graham Hunter is a Spanish-based football journalist and author of 'Barca: The Making of the Greatest Team in the World'.
When I began my career, in the late 1980s, early 1990s, worldwide there were fewer people who considered themselves as fans of Real Madrid or Barcelona.
It was not an unknown phenomenon, but both clubs have since strategically ballooned their audience and fan base around the world and now there is outright vehement adoration and love for either Real or Barca from people who have never been to Spain and will never go to an El Clasico.
I don't believe it's using adjectives for the sake of it, El Clasico is like theater, it's like opera, the grand themes are all there.
Year in, year out, almost without exception, certainly with a higher strike rate than any other game in the world -- even the Champions League final -- El Clasico delivers. The last time there was a goalless draw was in 2002.
It gives you quality football, dramatic football, it gives you that certain thing that pulsates from the football pitch to the audience in the ground and through a television set. It remorselessly delivers and I think that's a key factor in El Clasico's appeal.
If we're absolutely truthful about AC Milan versus Inter Milan in Italy, or Germany's Bayern Munich against Borussia Dortmund, or the big English games, you can see exceptional contests, but not as often as El Clasico.
Reporting on the match is just thrilling. It's a brilliant test of our ability, your learning and your communication powers.
The challenge for each and every one of us is to be at our best. If your stomach is not full of butterflies, if you're not genuinely outright nervous -- did I predict it properly, have I analyzed it properly -- then you shouldn't be in the industry. El Clasico is like a cattle prod to the senses.
On Saturday, I think Real will probably reignite the league and will show that when they're on form, currently, they're a better side than Barca.
A Barca win doesn't make them league champions, but a Barca win means Real won't win the title. I have a sneaky suspicion that Real will win this, and I've a sneaky suspicion that Real are legitimate candidates to become champions again.
As far as the impact of Catalan independence vote on this match, irrespective of where you stand in the debate, not one of Barcelona's players has come out and demanded independence.
But, when it comes to going to the capital against savvy Real Madrid support, it will be used to heighten the booing, whistling and the tension, to see whether that will put the Barca players off their stride.
The Real fan -- 'If we lose Christmas is going to be bad'
Colombian born Majin A. Hemer Sierra, 33, is president of the 124-member strong official Real Madrid fan club in Atlanta.
Sometimes Americans talk to me, people who don't watch soccer, and think it's just a game, and I try to explain to them that it's not only 22 guys kicking a ball.
We're talking about two different ways of seeing things for everything: how to play football, politics, the way you think. Our way of seeing things, as Real Madrid fans, is different to Barcelona fans. We are used to being the best and we say that being a Real Madrid supporter means you're already a winner in anything! I've been receiving text from friends about the match since Monday and every day the intensity gets higher.
The match is 7am Atlanta time, and our regular Irish pub usually opens at 11am, but it will open early on Saturday. The owners have been gracious enough to say they'll have the doors open and the TV on in enough time before kickoff.
Personally, I'm OK in the week leading up to an El Clascio but from an hour prior to kick-off that's when I start to get nervous.
I'm Catholic so I'll just do the cross and pray. People have their own rituals. I have a member who wears the same Real Madrid jersey for El Clasicos, he'll only wear that jersey for El Clasico. Many of our members have things they do before an El Clasico.
Nobody wants to lose an El Clasico. If we lose, I know for sure that my Christmas and the rest of next week is going to be horrible.
Even though we're in America we see ourselves as part of Real Madrid and the club makes us feel that way. In football, you feel the same whether you're inside the stadium or not.
The passion here is the same as in Madrid - if not more so because most of the people in the stadium are already used to seeing Real every weekend and have seen many Clasicos but, for us, it's something different.
Additional reporting by Duarte Mendonca