At the 2010 FIFA World Cup, Lugano led Uruguay to an impressive fourth-placed finish. Lugano also captained Uruguay to victory at the 2011 Copa América, playing in all six games for the eventual champions. On 2 September 2011, Lugano scored a goal as Uruguay defeated Ukraine 3–2 in an international friendly away in Kharkiv. In his next call up to the national side, on 7 October 2011, Lugano netted a brace in Uruguay's 4–2 defeat of Bolivia in World Cup qualifying.