Barcelona go into the Champions League quarter-final trailing 3-0 from the first leg.
Goals from Paulo Dybala (2) and Giorgio Chiellini mean the Catalan giants face an uphill battle to make the last four.
Should they progress, it would come just over a month after they historically overcame a 4-0 first leg battering from Paris Saint-Germain to go through.
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They battered their fierce rivals 6-2 in the Santiago Bernabeu back in 2009.
Messi and Thierry Henry bagged braces with Gerard Pique and Carles Puyol also getting on the scoresheet.
Two years after Real spent £80million on Cristiano Ronaldo, Barcelona thumped the Spanish giants again.
With Jose Mourinho in charge, Madrid were beaten 5-0 on a chastening night at the Nou Camp.
Lionel Messi scored twice as Barcelona thumped Real Madrid in 2009
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Messi was again the star of the show, pulling the strings and helping Xavi, Pedro, David Villa (2) and Jeffran run riot.
Barcelona also hope their 4-0 win over Real at the Bernabeu in 2015 sees them overcome Juventus.
Luis Suarez (2), Neymar and Andres Iniesta ensured Madrid were swept aside in their own back yard.
Barcelona are also desperate to stop Real from winning the Champions League.
Should they do so, they would make history by becoming the first club to retain the trophy in its modern format.