Vizcaíno signed with the Astros on November 20. In 2001, he hit .277 with 71 hits and 14 runs batted in. He appeared in three games in the 2001 National League Division Series, he was 1 for 6 as Houston was defeated by the Atlanta Braves. In 2002, he hit .303 with five home runs and 37 runs batted in 125 games. In 2003, Vizcaíno appeared in only 91 games, where he collected 26 runs batted in. In 2004, Vizcaíno rebounded, hitting .274 and playing in 138 games at shortstop while Adam Everett was out with a broken wrist. In the 2005 National League Division Series, Vizcaíno went 0-for-5 in two games. Despite his lack of productivity, the Astros defeated the Braves in 5 games. In the 2005 National League Championship Series against the St. Louis Cardinals, Vizcaíno did not fare better, again going hitless. In the 2005 World Series, Vizcaíno collected one hit, one walk, and two runs batted in. In Game 2 of the 2005 World Series, he came close to repeating his 2000 World Series walk-off moment when he hit a two-run single with two outs in the ninth inning to tie the game. Following his game tying hit for the Houston Astros, Vizcaíno stayed in the game at shortstop for the bottom of the ninth, and on the way out to his position, he realized he had forgotten his cap and had to return to the dugout to get it. After the game Vizcaíno commented "It was crazy, I ran out there without [a cap], and when I realized it, I felt funny. More camera time for me, I guess." The Astros went on to lose when Scott Podsednik homered in the bottom of the inning and overshadowed Vizcaíno's heroics. In Game 3 of that year's Series, Vizcaíno played the entire game, which broke the record for the longest game in World Series history on October 25, 2005.