Spanoulis was a member of the Greek senior team that competed at the 2006 FIBA World Cup, and he helped to lead the Greek team to the silver medal, as they finished in second place in the tournament. In the semifinals game against Team USA, he was the game's second-leading scorer, with 22 points (after Carmelo Anthony, who scored 27 for the USA), and along with his teammate, Theo Papaloukas, led Greece to victory over the USA, by a score of 101–95.