Serena Williams defeated Victoria Azarenka in the final, 6–1, 6–3 to win the women's singles tennis title at the 2012 Madrid Open. It was Azarenka's second consecutive runner-up finish at the event.
Petra Kvitová was the defending champion, but lost to Lucie Hradecká in the second round.
Seeds
Victoria Azarenka (final) Maria Sharapova (quarterfinals) Petra Kvitová (second round) Agnieszka Radwańska (semifinals) Samantha Stosur (quarterfinals) Caroline Wozniacki (third round) Marion Bartoli (first round) Li Na (quarterfinals)
Serena Williams (champion) Vera Zvonareva (first round) Francesca Schiavone (first round) Angelique Kerber (third round) Ana Ivanovic (third round) Dominika Cibulková (first round) Jelena Janković (first round) Maria Kirilenko (second round)