The Argentine is back in his homeland, where he conducted a revealing interview about his future, and it has been confirmed that he will not return to training until the beginning of next year.
Messi's absence may lead to a tactical rethink by Ronald Koeman, who used three at the back to good effect in the win over Valladolid just before Christmas.
With Sergi Roberto and Gerard Pique still out, defensive options remain limited and so it's unclear whether Koeman will pivot to a back four or retain the back three.
Assuming he opts for four, he will employ Sergino Dest and Jordi Alba at full-back, while Clement Lenglet will play alongside with Ronaldo Araujo or Oscar Mingueza, with Samuel Umtiti probably on the bench.
Up ahead the electric Pedri is making himself a guaranteed starter these days, with Frenkie De Jong and, Miralem Pjanic likely to play behind him.
Up ahead is a little more difficult to judge. Both Antoine Griezmann and Philippe Coutinho were benched for the Valladolid win but without Messi one of the duo is likely to come back into the side. Martin Braithwaite will likely lead the line once again.