Ruben Alcaraz got both goals for Hospitalet who drew 2-2 at the Calderon against an Atletico side with most of their regular players rested following a 3-0 first leg victory.
Mandzukic, who is suspended for the trip to Athletic Bilbao this weekend, pounced midway through the first half but Alcaraz brought the team from the Spanish third tier back on level terms with a deflected shot after 66 minutes. The Croat restored Atletico's lead with a diving header from a Koke cross before Alcaraz hit a swerving shot into the roof of the net to give some joy for the visitors.
Atletico now face Real, who beat them in the semi-finals last season, in the last 16. "This year we have only lost one game at home at the Calderon and this shows the work of the players," Simeone told a news conference.
"Hopefully we can keep going the same way. In terms of this game I am happy with what I saw. We started well and scored while in the second half the Hospitalet players responded well.
"They had a bit of luck with their first goal and the second was something special."
Elsewhere, Malaga overcame Deportivo La Coruna 5-2 on aggregate, Athletic Bilbao beat Alcoyano 2-1 overall and Elche advanced after a 1-0 advantage from their two games against Valladolid.
(Editing by Greg Stutchbury)
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