Tito Vilavnova's side allowed a 2-0 lead to slip away to Real Sociedad, who capped a brave fight back with an injury time goal from Imanol Agirretxe, reports Xinhua.
Things had been running smoothly for Barca after Leo Messi and Pedro Rodriguez had put them 2-0 up but two goals from Chori Castro, the second of which took a big defection off Javier Mascherano levelled the scores and with Barca playing with 10 men after Gerard Pique's sending off, Agirretxe was on hand to inflict the first defeat of the season on the league leaders, who had previously looked unbeatable.
Atletico Madrid took advantage of Barca's defeat to close the gap at the top of the table to eight points with a comfortable 2-0 win against Levante which came thanks to goals from Adrian Lopez and Koke, who scored a magnificent curling effort to assure the points.
The bad news for Atletico was that top scorer, Radamel Falcao had to leave the game in the second half with a muscle problem that will keep him out of action for three weeks.
Real Madrid might have expected a difficult trip to Valencia's Mestalla Stadium but were 5-0 up after 45 minutes after Cristiano Ronaldo and Angel Di Maria both netted a brace while Higuain scored in the opener.
The second half was a non-event as both sides conserved their strength for when they meet again in midweek in the return leg of their Copa del Rey quarterfinal.
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Malaga look to be struggling on their opening league matches of the season and saw two more points escape with a 1-1 draw against struggling Celta Vigo.
Martin Demichelis put Malaga ahead but Augusto Fernandez gave Celta a valuable point 15 minutes from time.
Celta were one of several sides fighting against relegation to enjoy a good weekend. Granada moved out of the bottom three with a 2-0 win at home to Rayo Vallecano. A Jordi Amat own goal and a shot from loanee, Recio, 10 minutes from time gave Granada three valuable points against a side that had won their four previous games.
Meanwhile Osasuna climbed off the bottom of the table thanks to a 2-1 home win against Deportivo la Coruna, who replace them in the last place. Kike Sola and Nino scored the goal for Osasuna while former Osasuna midfielder Javier Camunas netted an injury time consolation for Deportivo.
Elsewhere, Zaragoza have dropped into the relegation mix due to a 2-0 defeat away to Valladolid. Javi Guerra and Oscar Gonzalez gave Valladolid a comfortable victory while Jose Antonio Reyes and Adrian Colunga assured a share of the points in the match between Getafe and Sevilla.
The round of matches finishes Monday with fourth place Betis favorites to take three points off Athletic Club Bilbao.