After a goalless draw in the first game last week, the two rivals meet at Santiago Bernabeu with Atletico knowing an away goal will give them a massive opportunity to reach the last four.
Simeone's side have not lost to Real - who will be without Karim Benzema, Gareth Bale and Luka Modric - since last season's Champions League final, a run of seven games in all competitions, and he is confident Atletico can extend that unbeaten streak.
"We have no pressure, we have responsibility, pressure is something else," said the Argentine. "We have to enjoy these occasions because we may never experience them again.
"Real Madrid played like we expect them to [in the first half of the first leg]. I'm more interested in how we can hurt them, and am not thinking about Madrid's injury problems.
"The replacements - who have spent a long time on the bench for Madrid - are also dangerous. We are focused on our preparation, we are only thinking about ourselves.
Simeone has a fitness concern over Mario Mandzukic ahead of the clash, but will give the Croatian striker as much time possible to be ready.
"Mandzukic trained well [on Monday]," he added. "Let's see how he feels. We hope he will be okay to play."
