Barcelona could not overcome the absence of Lionel Messi and other regular starters on Thursday, losing 2-1 at Levante in the first leg of the Copa del Rey's round of 16.
Barcelona's second-stringers struggled from the start in Valencia, escaping an even greater defeat only because Levante's forwards squandered some clear scoring chances.
The return game is next Thursday at Camp Nou Stadium in Barcelona when the four-time defending champion is expected to have some of its starters back in action after they were rested this week.
Levante took the lead early with a close-range header by Uruguayan defender Erick Cabaco in the third minute, and striker Borja Mayoral scored the second goal with a low cross-shot in the 18th.
The hosts kept threatening throughout the match, taking advantage of a Barcelona defence that was without Gerard Pique and Jordi Alba. Newly signed Colombian player Jeison Murillo was making his club debut in central defence.
"We got off to a great start," Mayoral said. "We pressed early because we knew they were not used to playing together."
Without Messi and Luis Suarez in the attack, the Catalan club had difficulties creating scoring opportunities. The trio of Philippe Coutinho, Ousmane Dembele and Malcom was largely ineffective, and the team's lone goal came late with a penalty kick converted by Coutinho in the 85th after substitute Denis Suarez got past a defender and was fouled inside the area.
"In the second leg hopefully we will take advantage of Coutinho's goal," Murillo said.
Barcelona routed Levante 5-0 in Valencia in a league match in December.
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Sevilla, a Copa finalist in two of the last three seasons, cruised to a 3-1 away win over Athletic Bilbao with goals by Manuel "Nolito" Agudo, Andre Silva and Wissam Ben Yedder.
Mikel San Jose scored for Athletic, which is fighting against relegation in the Spanish league.
The teams face each other again in the league on Sunday. Their second-leg match in the Copa is next week in Seville.
Also Thursday, Real Betis was held by visiting Real Sociedad to a 0-0 draw.
On Wednesday, Real Madrid defeated Leganes 3-0 at home, while Atletico Madrid drew 1-1 at Girona.