Second leg matches take place on 10th November except where stated. (22.09.10)
Results were as follows (aet - after extra time, pso - penalty shoot out, teams qualifying in bold): match reports
| Real Madrid Granero, Higuaín, Cristiano Ronaldo, Benzema (Pen), Xabi Alonso |
5-1 | Murcia Pedro (Pen) |
| Sevilla Alfaro, Rodri, Bernardo, Cigarini, José Carlos, Acosta |
6-1 | Real Unión Eneko Romo |
| Valencia Isco (2), Vicente, Feghouli |
4-1 | Logroñés Osado |
| Barcelona Nolito, Milito, Pedro, Bojan, Messi |
5-1 | Ceuta Guzmán |
| Villarreal Jefferson Montero, Altidore |
2-0 | Poli Ejido |
| Atlético Madrid
Fran Mérida |
1-1 | Univ. Las Palmas Aridane |
| Getafe |
0-0 | Portugalete |
| Zaragoza Jarosik |
1-2 | Betis Contini (OG), Rubén Castro |
| Levante Caicedo |
1-2 | Xerez Antoñito (2, 1 Pen) |
| Racing Santander Iván Bolado, Kennedy, Edu Bedía |
3-1 (aet) |
Córdoba Luque (Pen) |
| Athletic Bilbao Gabilondo, Orbaíz |
2-0 | Alcorcón |
| Espanyol Osvaldo |
1-1 | Valladolid Barragán (Pen) |
| Almería Goitom, Ulloa |
2-1 | Real Sociedad Agirretxe |
| Deportivo Riki, Lassad |
2-1 | Osasuna Lekic |
| Málaga Eliseu, Edinho, Sebas Fernández |
3-2 | Hércules Portillo, Abel Aguilar |
| Sporting Gijón Bilic (Pen), Juan Muñiz |
2-2 | Mallorca Nsue (2) |