Messi netted a hat-trick and provided an assist in Barca's 4-2 La Liga win over Sevilla on Saturday and he will be eager to produce once more, having missed the first leg of this Copa Del Rey semi-final through injury.
That match finished 1-1 at Camp Nou three weeks ago, where Malcom scored for the hosts and Lucas Vazquez netted for Santiago Solari's men.
Messi is La Liga's top scorer by some distance this season, nine goals ahead of team-mate Luis Suarez who is the second-most prolific marksman in the Primera Division.
Messi has three goals in his last three visits to the Bernabeu where he netted a penalty in La Liga last season. It is interesting to see that the two shortest-priced options to score are both visiting players, with Suarez offered at evens (2.00).
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The hosts' chances of finding the back of the net will rest greatly on Karim Benzema and the Frenchman hit the 20-goal mark for the season in the weekend win over Levante and is priced at 5/4 (2.25) to find the back of the net on Wednesday evening.
The 31-year-old has not been overly prolific in this fixture, scoring in just one of the last eight Clasicos, although the presence of Cristiano Ronaldo in the team meant that Benzema was less of a goalscoring protagonist.
Gareth Bale meanwhile is available at 8/5 (2.60) although his place in the team is far from guaranteed. The Welshman did not start the first leg at the Camp Nou, with Brazilian teenager Vinicius Junior preferred in his place.
The 18-year-old has shown himself to be an exciting prospect, even if his finishing has been a little wayward, and he can be backed at 11/5 (3.20) to score his first ever Clasico goal.
Tips and predictions
With Messi in devastating form there could be some interest in the price of 10/3 (4.33) for him to score two or more goals, something he has managed on seven occasions in this fixture in all competitions.
Also well worthy of consideration is backing Karim Benzema to score Madrid's first goal at 9/4 (3.25), with this selection paying out in the last five games where the Frenchman has scored.
Odds correct at the time of writing. Please gamble responsibly.