Barcelona was held at Sevilla to 0-0 for its first stumble since the resumption of play in the Spanish league following a three-month stoppage for the COVID-19 pandemic.
The slip gives Real Madrid the chance to pull level atop the Spanish league with Barcelona. Madrid trails Barcelona by three points before it visits Real Sociedad on Sunday to complete round 30 of 38. Madrid holds the head-to-head goal difference with Barcelona in the case of a tie.
Barcelona defender Gerard Pique said the two points the defending champions left in Seville on Friday could be decisive.
"It is going to be difficult to win this league because we depend on the results of others now, and I don't think Madrid is going to drop many points," Pique said.
"We lost a chance today. And seeing how we have played (...), it is going to be difficult." Coach Quique Setién, however, said the fight was far from over.
"We knew beforehand that it would be difficult to win all the games left, practically impossible, and that this was one of the toughest matches we faced," Setién said.
"It is frustration of the moment. (.) I am sure (Pique) will feel different tomorrow, and I am sure that Madrid will drop points, too. We have to be optimistic."
Lionel Messi went closest to breaking the stalemate when his first-half free kick was cleared on the line by defender Jules Kounde, leaving the Argentina star on 699 career goals for club and country.
Barcelona's all-time leading scorer was stifled by Sevilla's defense anchored by former Manchester City midfielder Fernando. Messi had scored in the previous two matches, both Barcelona wins, since the league resumed.
Sevilla, which played without its normally very loud fans at its Sánchez Pizjuán Stadium as mandated by health officials in all league games, remained in third place at 10 points behind Madrid.
Villarreal moved into contention for a top-four finish and a Champions League berth after it won at Granada 1-0 thanks to Gerard Moreno's early strike. A third straight victory left Villarreal in seventh place but just two points out of fourth.
Leganés snatched a 1-1 draw at Mallorca in a match between two teams in the relegation zone. Both goals came from free kicks, with Salva Sevilla putting Mallorca early and Óscar Rodríguez equalising with three minutes left.