Having won the first leg 5-0 at home last week, Barcelona started just three regulars: forward Lionel Messi, midfielder Xavi Hernandez and defender Gerard Pique.
Betis, the second-division leader, built a 2-0 lead on goals by Jorge Molina in the second and seventh minutes. It was the first time Barcelona had trailed in a match since Oct. 16, when it rallied for a 2-1 league victory over Valencia.
Messi, the two-time FIFA player of the year, closed the gap in the 38th minute with his 32nd goal of the season, but Arturo "Arzu'' Garcia made it 3-1 in first-half injury time.
Messi had a chance to pull Barcelona within a goal again in the 54th minute but sent his penalty kick over the crossbar.
A day after coach Pep Guardiola's 40th birthday, Barcelona fell to 25-2-6 in all competitions this season, with its only other loss 2-0 at home to Hercules in the league on Sept. 11.
In the semifinals, Barcelona plays Almeria - a team it defeated 8-0 in the league this season. The other semifinal has defending champion Sevilla playing Real Madrid or Atletico Madrid, which trails 3-1 going into Thursday's second leg. (sportsillustrated)
RESULT:
Real Betis: 3
FC Barcelona: 1
GOALSCORERS:
Real Betis: Molina (2′), Molina (7′), Arzu (45+2′)
FC Barcelona: Messi (38′)
LINEUPS:
FC Barcelona: Pinto, Adriano, Piqué, Milito, Maxwell, Mascherano, Keita, Xavi, Afellay, Bojan and Messi
Real Betis: Casto, Isidoro, Belenguer, Roversio, Nacho, Iriney, Salva Sevilla, Ezequiel, Arzu, J. Pereira and Molina
SUBSTITUTES:
Real Betis: Goitia, F. Vega, Juanma, Cañas, Israel, Juande, and Miki Roque
FC Barcelona: Valdés, Abidal, Bartra, Busquets, Villa, Iniesta and Jeffren
SUBSTITUTIONS:
Real Betis: Cañas on for Iriney (62′), F. Vega on for Ezequiel (65′), Israel on for Molina (79′)
FC Barcelona: Busquets on for Xavi (78′), Abidal on for Afellay (78′), Jeffren on for Bojan (86′)
CAUTIONS:
Real Betis: Isidoro (53′), J. Pereira (78′)
FC Barcelona: Adriano (30′)