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| 14.12.2021 | 18:00 | ADO Den Haag | - | VV Gemert | 4:2 (1:1) | |
| 18:00 | PEC Zwolle | - | MVV | 4:0 (2:0) | ||
| 20:00 | FC Emmen | - | Excelsior Maassluis | 0:1 (0:0) | ||
| 21:00 | Telstar | - | SV Spakenburg | 5:3 (2:1, 3:3) n.V. | ||
| 21:00 | NAC Breda | - | FC Utrecht | 3:2 (0:1) | ||
| 15.12.2021 | 18:00 | Harkemase Boys | - | RKC Waalwijk | 0:5 (0:2) | |
| 18:00 | FC Twente | - | Feyenoord | 2:1 (0:0, 1:1) n.V. | ||
| 18:00 | AZ Alkmaar | - | Heracles Almelo | 4:1 (2:1) | ||
| 18:00 | Vitesse | - | Sparta Rotterdam | 2:1 (1:1) | ||
| 20:00 | SBV Excelsior | - | FC Groningen | 2:4 (1:1, 2:2) n.V. | ||
| 21:00 | Go Ahead Eagles | - | Roda JC Kerkrade | 2:0 (2:0) | ||
| 21:00 | PSV Eindhoven | - | Fortuna Sittard | 2:0 (1:0) | ||
| 21:00 | AFC Ajax | - | BVV Barendrecht | 4:0 (2:0) | ||
| 16.12.2021 | 18:00 | SC Cambuur | - | NEC Nijmegen | 1:2 (0:2) | |
| 20:00 | Achilles Veen | - | DVS'33 | 0:2 (0:1) | ||
| 21:00 | sc Heerenveen | - | De Treffers | 2:0 (0:0) |
