Pep Guardiola's side, who have won the Cup a record 24 times, hammered Atletico 6-1 at the Nou Camp back in October and have trampled over all their closest challengers to open up an 11-point lead at the top of the league standings.
Atletico's 15-match unbeaten run in all competitions ended in a 3-1 defeat away to Valencia on Saturday.
"We are going to prepare well for the game to prove that Barca are not a team of extra-terrestrials," Atletico's French striker Florent Sinama Pongolle said.
"We'll see if, as they say in boxing, we can give them a knockout blow in the first match."
Atletico welcome captain Maxi Rodriguez and chief playmaker Maniche back after missing the Valencia game but coach Javier Aguirre said striker Sergio Aguero will start on the bench.
Barca travel without the injured Carles Puyol, Rafael Marquez and Aleksandr Hleb, and have rested Victor Valdes, Xavi and Samuel Eto'o. Forward Lionel Messi returns after being rested for Saturday's 3-1 win over Real Mallorca.
On Wednesday, there are five more first legs including holders Valencia's trip to face Racing Santander and the 2007 winners Sevilla's match at home to Deportivo Coruna.
The only remaining non-Primera Liga clubs Real Union and Poli Ejido of the Segunda B (third tier) are at home to Real Betis and Espanyol respectively.
Union knocked out Real Madrid and Ejido beat Villarreal in the last round. In the fifth match promoted Sporting Gijon host Real Valladolid.
The northern derby between the Primera Liga's bottom club Osasuna and 23-times winners Athletic Bilbao takes place on Thursday, when struggling Real Mallorca play host to Hugo Sanchez's Almeria.
The second legs take place on January 14 and 15.
