Alfredo di Stefano
The 26-year-old Argentine netted for the 19th time against Real Madrid in Sunday's Liga clash at the Santiago Bernabeu, thus moving him one clear of his compatriot in the all-time standings.
Los Blancos icon Di Stefano hit 18 goals in 30 Clasicos between 1953 and 1964, but Messi, with his strike just before halftime in Sunday's Clasico, has now surpassed that total in just 27 games between the two great Liga rivals.
Messi opened his Clasico account with a sensational hat trick - the last player to do so in the fixture - in a 3-3 draw at Camp Nou on March 10, 2007.
He has never looked back, netting a fine double in a stunning 6-2 dismantling of Madrid before its own fans at the Bernabeu in May 2009, while the four-time Ballon d'Or winner also scored both goals in the Blaugrana's 2-0 win in the away leg of the 2011 Champions League semifinals.
Messi equaled Di Stefano's record with his 17th-minute strike in Barcelona's 2-1 Liga loss in the Spanish capital on March 2 of last year.
However, Sunday night's strike at the same venue means that he has now taken outright possession of one of the Clasico's most prestigious records.