Cain was called up to the Giants on August 26, 2005, to join their rotation. He made his major league debut on August 29, at the age of 20 against the Colorado Rockies; he gave up only three hits and two runs in five innings but still ended up losing the game. He earned his first major league win on September 4 allowing one run in seven innings against the Arizona Diamondbacks. He notched his first complete game, a two-hitter, against the Chicago Cubs on September 9. Cain finished his first season with seven starts over innings in which he posted a 2–1 record, 30 strikeouts, a 2.33 ERA, a 0.928 walks plus hits per inning pitched (WHIP), and a minuscule .151 opponent batting average.