[1] His first experience as an international referee came on 4 September 2004, between Turkey and Georgia, in a preliminary qualifier for the 2006 FIFA World Cup.

On 21 August 2005, Medina Cantalejo referred the Russian Premier League match between CSKA Moscow and Zenit St.Petersburg.

[4] He subsequently officiated three matches at the 2006 FIFA World Cup: Germany v. Poland, Netherlands v. Argentina, and Italy v. Australia.

In the round of 16 match between Italy and Australia, he made some controversial decisions, including showing Italy's Marco Materazzi a straight red card for a challenge on Australia's Mark Bresciano, and later awarded an injury time penalty to Italy after adjudging Australian defender Lucas Neill to have fouled Italian full back Fabio Grosso in the penalty area; Francesco Totti converted the ensuing spot kick to score and give the Italians a 1–0 victory.

[11] Medina Cantalejo was chosen to officiate the 2008 UEFA European Championship qualifying match between England and Russia.