Messi has edge in battle of world's best
The third man in the running to win that award, Xavi, will also be on the pitch at the Santiago Bernabeu on Saturday, but for all his class, it is hard to envisage the midfielder finishing above the two men who are widely recognised as the best in the world.
The importance of this Clasico is huge - the winners of the season's first showdown have gone on to win the title in each of the last seven campaigns - and it is far more than simply a showdown between Messi and Ronaldo. Jose Mourinho's side have won their last 15 games in all competitions, equalling a club record, and can go six points clear with a game in hand with a victory against the defending champions.
In addition, Barcelona's away record makes it hard to envisage them winning in the capital - Pep Guardiola's men have won just twice in six games on the road this season, both by a 1-0 margin. And Messi, the winner of last year's Ballon d'Or, is not the same player away from Camp Nou, having scored just one of his 17 goals in La Liga on the road.
But then the 24-year-old Argentine just loves this fixture, having netted 13 times in 15 previous meetings with Real Madrid, and he loves coming up against Iker Casillas, having scored more times against the Spain captain than any other goalkeeper in the Spanish top flight.
Prolific goalscoring records
La Pulga - 'The Flea' - is also one of only two players to score in five consecutive Clasicos at the Bernabeu, with the other being the great Real legend of the 1980s, Hugo Sanchez.
Ronaldo, meanwhile, has picked up where he left off in the last campaign, joining Messi atop the scorers' charts having won the Pichichi with a record 40 goals in 2010/11.
Last season was also notable for the Portuguese forward as he scored against Barcelona for the first time - his penalty in the 1-1 draw at the Bernabeu in April ending a long barren run against the Catalans both with Manchester United and Madrid.
Only days after scoring that goal, the 26-year-old won the Copa del Rey for his side with a superb headed goal deep in extra time in the final against Barcelona.
But Ronaldo has just three goals in nine appearances against Barcelona and since the Copa del Rey disappointment, Messi has scored a wonder goal in the first leg of the UEFA Champions League semi-final between the teams, and also decided the domestic Super Cup in August with a last-gasp strike.
Messi's superior record in head-to-head meetings helps make it hard to see past him retaining the Ballon d'Or, although Ronaldo has always refused to entertain talk of a direct rivalry between the two. "I am not obsessed about this business of a direct rivalry between Messi and I," he said last season.
"I feel nothing more towards him than I do towards any other player. I feel absolutely no envy towards Messi. My priority is to win as many Champions Leagues and Spanish titles with Real Madrid as possible, not the Ballon d'Or."
Messi is similarly taciturn when pressed on the subject. "Congratulations to him for winning the Pichichi," said the Argentine just before May's Champions League final, in which he played a starring role.
"You never say no to an individual award, but winning trophies together as a team comes first. The joy that it brings is incomparable. I wouldn't exchange any of his trophies for the ones that I have won."
Both men prefer to do their talking on the pitch, even if Messi has always spoken louder in this fixture.