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| 06.10.2021 | 15:00 | Diagoras FC | - | AE Lárissa | 1:2 (0:1, 1:1) ap | |
| 15:00 | AO Ypatou | - | AO Trikala | 0:1 (0:0, 0:0) ap | ||
| 15:00 | Anagennisi Karditsa | - | Almopos Arideas | 3:1 (0:0, 0:0, 1:1) tab | ||
| 15:00 | Kozani FC | - | Agios Nikolaos | 4:5 (1:1, 1:1, 1:1) tab | ||
| 15:00 | Levadiakos | - | PS Kalamata | 2:0 (0:0) | ||
| 15:00 | Niki Volou FC | - | Ergotelis | 2:0 (0:0) | ||
| 15:00 | Panachaiki GE | - | AO Egaleo | 1:0 (0:0) | ||
| 15:00 | AO Proodeftiki | - | Xanthi FC | 0:2 (0:1) | ||
| 15:00 | Panserraikos | - | AEP Iraklis FC | 2:1 (0:0) |
