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| 20.10.2021 | 14:00 | FC Struga | - | FK Borec | 5:4 pn. | |
| 14:00 | Akademija Pandev | - | Makedonija GP | 3:5 pn. | ||
| 14:00 | KF Shkëndija 79 | - | FK Renova | 5:0 | ||
| 14:00 | FK Bregalnica Štip | - | FK Ohrid | 4:0 | ||
| 14:00 | FK Belasica | - | Sileks Kratovo | 2:4 | ||
| 14:00 | FK Pelister | - | FK Rabotnički | 5:4 pn. | ||
| 14:00 | KF Shkupi | - | GFK Tikvesh | 1:0 | ||
| 14:00 | Vardar Skopje | - | FK Skopje | 4:2 pn. |
