The Spanish league is barely three months old, but Real Madrid's title defence is in serious danger after Real Betis midfielder Benat Etxebarria struck from long range to deal last season's champion a 1-0 loss on Saturday.
Madrid appeared to have put its struggles from earlier this season well behind it after stringing together five straight wins, but even with Cristiano Ronaldo, Karim Benzema and Kaka on the pitch, it failed to break through a Betis defence that had lost by four or more goals three times this season.
Jose Mourinho's team is in third place and can find itself an imposing 11 points behind Barcelona if the league leader wins at Levante on Sunday.
The largest deficit ever overcome by a team that went on to win La Liga was eight points by Rafa Benitez's Valencia in 2004.
A stern Mourinho acknowledged that it would be "difficult" to repeat as domestic champions.
"I understand that our fans are pessimistic. It is very possible that we will arrive to the end of December 11, 12, 13 points behind," he said. "But it is still possible. We have to try to cut and cut and cut into (Barcelona's) lead."
After being routed 5-1 by Sevilla in the Seville derby just six days before, Pepe Mel's Betis appeared to be an easy target for a Madrid that had just eliminated English champion Manchester City from the Champions League and was unbeaten in eight rounds.
But Betis emerged victorious thanks to an impressive physical display that never wavered through 90-plus minutes.
"It was a tough week for both the team and our fans. We deserved this win," a breathless Etxebarria said. "We had a good game plan and worked hard in defence. They didn't have many clear scoring chances and we had some more on the break."
It was Betis' second win in 22 games in all competitions against Madrid since 2001.
Both sides' pressing style set a fast pace from the start at Benito Villamarin Stadium, but after Madrid's Sami Khedira missed a good look on goal Etxebarria netted what proved to be the winner 17 minutes in.
The Basque player picked up Angel Di Maria's wild clearance from the flank, dribbled around Khedira and beat goalkeeper Iker Casillas with right-footed shot from about 23 yards.
"I was fortunate the ball fell to me," said Etxebarria, a Spain international. "I controlled it and shot and it went in."
Madrid bombarded Betis' area with crosses, but came no closer before halftime than Di Maria's shots into the side and the top of the netting.
Mourinho sent on playmakers Luka Modric and Kaka at the start of the second half for Mesut Oezil and fellow Germany international Khedira.
And when the leveler didn't come, the Portuguese manager soon threw forward Jose Callejon into the mix.
Yet even with all its firepower, Madrid couldn't convert its scarce opportunities while giving up chances to Betis' Salva Sevilla and Ruben Castro on counterattacks.
The nearest Madrid came was a Kaka shot that drew a diving parry from goalkeeper Adrian San Miguel, who bounced back in fine form from his woeful performance in last week's loss at Sevilla.
Madrid only dropped seven points away from Santiago Bernabeu Stadium last season en route to the title. It has already relinquished 11 points on the road through 13 rounds this campaign.
Also, Malaga outclassed a drab Valencia 4-0 thanks to a goal and assist by midfielder Francisco Portillo in Saturday's meeting of two of Spain's sides to reach the knockout rounds of the Champions League.
Leonardo Carrilho's strike three minutes from time sparked Rayo Vallecano to a 2-0 home win over Mallorca, while Valladolid broke a streak of three home draws by beating Granada 1-0 thanks to Angola striker Manucho's second-half goal.
Second-place Atletico Madrid hosts Sevilla on Sunday, while Espanyol hosts Getafe and Deportivo La Coruna visits Athletic Bilbao. Real Zaragoza plays Celta Vigo on Monday.
Real Sociedad drew 0-0 with Osasuna at home on Friday.