Roger Federer defeated Fernando González in the final, 7–5, 6–1, 6–0 to win the singles tennis title at the 2006 Madrid Open.

Rafael Nadal was the defending champion, but lost in the quarterfinals to Tomáš Berdych.

This tournament marked the first professional-level match played between Novak Djokovic and Andy Murray, who would go on to play a total of 36 ATP Tour-level matches against each other; Djokovic won their third-round encounter.

A champion seed is indicated in bold text while text in italics indicates the round in which that seed was eliminated.

All sixteen seeds received a bye into the second round.