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GMT 01:00
| 16.12.2021 | |||
| 21:00 | Albacete Balompié | 0-1 | Cádiz CF |
| 21:00 | Atl. Mancha Real | 1-0 | Granada CF |
| 21:00 | Atlético Baleares | 5-0 | Getafe CF |
| 21:00 | Deportivo La Coruña | 1-2 | CA Osasuna |
| 20:00 | CD Lugo | 1-2 | CD Mirandés |
| 19:00 | CD Arenteiro | 1-3 AET | Valencia CF |
| 19:00 | CF Talavera Reina | 2-4 AET | Real Betis |
| 19:00 | SD Amorebieta | 1-2 | UD Almería |
| 19:00 | UD Llanera | 0-6 | Real Mallorca |
| 15.12.2021 | |||
| 21:00 | Atlético Sanluqueño | 1-7 | Villarreal CF |
| 21:00 | CD Tenerife | 1-2 | SD Eibar |
| 21:00 | Unionistas Salamanca | 0-1 | Elche CF |
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