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| 26.10.2021 | 20:00 | KV Oostende | - | CS Onhaye | 8:1 (4:1) | |
| 20:30 | RWD Molenbeek | - | SV Zulte Waregem | 1:2 (1:1) | ||
| 20:30 | KV Mechelen | - | Union Saint-Gilloise | 2:1 (1:0) | ||
| 20:45 | Royal Excel Mouscron | - | Standard Liège | 0:1 (0:1) | ||
| 27.10.2021 | 20:00 | KAA Gent | - | Belisia Bilzen | 4:0 (3:0) | |
| 20:00 | St. Eloois-Winkel Sport | - | KRC Genk | 0:6 (0:4) | ||
| 20:00 | FCV Dender EH | - | KAS Eupen | 0:1 (0:1) | ||
| 20:00 | RFC Seraing | - | Sint-Truidense VV | 3:2 (2:2) ap | ||
| 20:00 | Sporting Charleroi | - | Lommel SK | 3:4 (0:0, 0:0, 0:0) tab | ||
| 20:00 | Royal Knokke FC | - | KV Kortrijk | 1:2 (0:0, 1:1, 1:1) tab | ||
| 20:30 | Royal Francs Borains | - | K Beerschot VA | 0:4 (0:1) | ||
| 20:45 | RAA La Louviére | - | RSC Anderlecht | 1:7 (1:4) | ||
| 20:45 | Lierse Kempenzonen | - | Oud-Heverlee Leuven | 1:2 (0:0) | ||
| 20:45 | Club Brugge KV | - | SK Deinze | 3:0 (0:0) | ||
| 28.10.2021 | 20:00 | Cercle Brugge | - | KVK Tienen | 3:0 (2:0) | |
| 20:45 | KVC Westerlo | - | Royal Antwerp FC | 2:1 (2:0) |
