Last year's 'Clasico' clashes were dominated by the Catalans, who won both games en route to winning La Liga. However, Madrid's appointment of Jose Mourinho has levelled the playing field and upped the ante ahead of Monday's big match.
Press Association Sport's Phil Barnett takes a look at the two key protagonists.
Over 100 metres on a track, the athletic Ronaldo would beat the impish Messi. Crucially, however, Messi can run with a ball nearly as quickly as he can without, while Ronaldo's close control is far less impressive. This makes them both more effective at different moments.
Ronaldo is a human highlight reel of superfluous flicks and tricks but is also able to utilise his impressive range of moves to affect matches. Messi has a far smaller bag of tricks and relies only on breathtaking natural ball control and dribbling - the best we've seen since Diego Maradona - to simply outstrip and outwit opponents.
Ronaldo has the edge in front of goal. Comfortable with both feet and strong in the air, his record is also more impressive than Messi's, thanks in part to his development into a more central, forward role. However, Messi is catching him up as he also matures into a more advanced position and the two are currently neck and neck - Ronaldo has 14 La Liga goals, Messi 13.
Ronaldo is bigger and stronger than Messi, who joined Barcelona when he needed growth hormone treatment as a boy and still bears a lightweight frame. The Portugal international can use his size to win balls in the air - when necessary - and maintain his performance for 90 minutes. Yet the diminutive Messi, who is nicknamed 'The Flea', is more robust when challenged, stays on his feet better and tracks back more often.
While Messi is perceived as meek and mild, he is a key figure in the Barca dressing room and coach Pep Guardiola has groomed him to become an understated leader. His infectious enthusiasm, honesty and boyish naivety win him as many admirers as his skills although his tendency to stay on his feet when fouled may frustrate the more cynical Barca supporters. Ronaldo is the polar opposite - tempestuous, sulky and scheming. This, though, represents his winning mentality and commitment to the cause - be it the team's or his own.
Big game mentality
Both players have been accused of failing to turn up when it matters at times in their career. Messi's goal in the 2009 Champions League final against Manchester United helped erase those doubts, while Ronaldo's woeful World Cup and startlingly ineffective performances against Barca last year leave question marks over his mettle.
Ronaldo is the machine, Messi the magician. The former's attributes stack up better on paper but Messi has the 'je ne sais quoi' which gives him the edge, however slight.