Massimo de Santis started refereeing at a young age, and after serving 15 years officiating in youth leagues, and then the third and fourth levels of the Italian League, he made his Serie A début in 1995. He went on to take charge of 159 top flight matches until his last game, between Juventus and Palermo, in 2006. He also refereed 103 Serie B matches, and in Serie A took charge of three Milano and two Torino derbies. He also refereed the 2001 Italian Cup final between Fiorentina and Parma. An international referee from 2000, de Santis won the Giovanni Mauro Award as Best Referee of the Year in 2003. He was involved in two matches at the 2004 Athens Olympics and refereed two UEFA Cup semi-finals, between Sporting Lisboa and AZ Alkmaar in 2005, and Sevilla and Schalke 04 a year later.