Villarreal returned in 2005, and ended up having another season shortened by an arm injury. He started the year with Triple-A Tucson before being called back up to the bigs on April 9. He pitched 1.2 scoreless innings on April 9 and left the next game against the Los Angeles Dodgers with a sore right shoulder. Villarreal had strained his rotator cuff, and the injury landed him on the DL until September 2. In his first game back in the majors, Villarreal surrendered a home run. He won a game on September 17, which was his first big-league victory since September 25, 2003. Villarreal finished the season with 2 wins and no losses, 5 strikeouts, and a 5.27 earned run average.