Spiezio, used as a pinch hitter and all-around reserve player as well as the primary backup to Scott Rolen at third base, had his best season since 2002 for the 2006 Cardinals, hitting 13 home runs and driving in 52 runs despite only getting 276 at bats. He would have another dramatic moment in the playoffs. With the Cardinals trailing, 6–4, in the seventh inning of Game 2 of the 2006 National League Championship Series, Spiezio hit a two-run triple to tie the score. The Cardinals went on to win the game and the series in seven games, then proceeded to win the 2006 World Series, earning Spiezio his second World Series ring.