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| I | Shakter Karaganda | - | Maccabi Tel Aviv | 1:2 (0:0) | ||
| V | Maccabi Tel Aviv | - | Shakter Karaganda | 2:0 (2:0) | ||
| I: 19.08.2021 15:00 | V: 26.08.2021 19:30 | Campeones: Maccabi Tel Aviv | ||||
| I | FC Flora | - | Shamrock Rovers | 4:2 (2:1) | ||
| V | Shamrock Rovers | - | FC Flora | 0:1 (0:0) | ||
| I: 19.08.2021 18:00 | V: 26.08.2021 20:45 | Campeones: FC Flora | ||||
| I | Qarabağ FK | - | Aberdeen FC | 1:0 (1:0) | ||
| V | Aberdeen FC | - | Qarabağ FK | 1:3 (0:2) | ||
| I: 19.08.2021 18:00 | V: 26.08.2021 20:45 | Campeones: Qarabağ FK | ||||
| I | Kuopion PS | - | 1. FC Union Berlin | 0:4 (0:3) | ||
| V | 1. FC Union Berlin | - | Kuopion PS | 0:0 (0:0) | ||
| I: 19.08.2021 18:00 | V: 26.08.2021 20:15 | Campeones: 1. FC Union Berlin | ||||
| I | Raków Częstochowa | - | Gante | 1:0 (0:0) | ||
| V | Gante | - | Raków Częstochowa | 3:0 (1:0) | ||
| I: 19.08.2021 18:00 | V: 26.08.2021 20:00 | Campeones: Gante | ||||
| I | FK Žalgiris | - | FK Bodø/Glimt | 2:2 (1:0) | ||
| V | FK Bodø/Glimt | - | FK Žalgiris | 1:0 (0:0) | ||
| I: 19.08.2021 19:00 | V: 26.08.2021 18:00 | Campeones: FK Bodø/Glimt | ||||
| I | Neftçi PFK | - | Maccabi Haifa | 3:3 (0:1) | ||
| V | Maccabi Haifa | - | Neftçi PFK | 4:0 (2:0) | ||
| I: 19.08.2021 19:00 | V: 26.08.2021 19:00 | Campeones: Maccabi Haifa | ||||
| I | Riga FC | - | Lincoln Red Imps | 1:1 (0:0) | ||
| V | Lincoln Red Imps | - | Riga FC | 3:1 (1:1, 1:1) pró. | ||
| I: 19.08.2021 19:00 | V: 26.08.2021 18:00 | Campeones: Lincoln Red Imps | ||||
| I | Viktoria Plzeň | - | CSKA Sofia | 2:0 (1:0) | ||
| V | CSKA Sofia | - | Viktoria Plzeň | 3:0 (1:0, 2:0) pró. | ||
| I: 19.08.2021 19:00 | V: 26.08.2021 19:00 | Campeones: CSKA Sofia | ||||
| I | LASK | - | St. Johnstone FC | 1:1 (0:1) | ||
| V | St. Johnstone FC | - | LASK | 0:2 (0:0) | ||
| I: 19.08.2021 19:00 | V: 26.08.2021 20:00 | Campeones: LASK | ||||
| I | Hapoel Be'er Sheva | - | Anorthosis Famagusta | 0:0 (0:0) | ||
| V | Anorthosis Famagusta | - | Hapoel Be'er Sheva | 3:1 (1:1) | ||
| I: 19.08.2021 19:00 | V: 26.08.2021 19:00 | Campeones: Anorthosis Famagusta | ||||
| I | CS FOLA Esch | - | FK Kairat | 1:4 (1:3) | ||
| V | FK Kairat | - | CS FOLA Esch | 3:1 (3:1) | ||
| I: 19.08.2021 19:30 | V: 26.08.2021 16:00 | Campeones: FK Kairat | ||||
| I | Basilea | - | Hammarby IF | 3:1 (1:0) | ||
| V | Hammarby IF | - | Basilea | 3:4 (0:0, 2:0, 3:1) pn. | ||
| I: 19.08.2021 19:30 | V: 26.08.2021 19:00 | Campeones: Basilea | ||||
| I | Trabzonspor | - | Roma | 1:2 (0:0) | ||
| V | Roma | - | Trabzonspor | 3:0 (1:0) | ||
| I: 19.08.2021 19:30 | V: 26.08.2021 19:00 | Campeones: Roma | ||||
| I | Rennes | - | Rosenborg BK | 2:0 (1:0) | ||
| V | Rosenborg BK | - | Rennes | 1:3 (0:2) | ||
| I: 19.08.2021 20:00 | V: 26.08.2021 19:00 | Campeones: Rennes | ||||
| I | RSC Anderlecht | - | Vitesse | 3:3 (2:1) | ||
| V | Vitesse | - | RSC Anderlecht | 2:1 (1:0) | ||
| I: 19.08.2021 20:00 | V: 26.08.2021 19:00 | Campeones: Vitesse | ||||
| I | PAOK Saloniki | - | HNK Rijeka | 1:1 (0:1) | ||
| V | HNK Rijeka | - | PAOK Saloniki | 0:2 (0:1) | ||
| I: 19.08.2021 20:00 | V: 26.08.2021 20:00 | Campeones: PAOK Saloniki | ||||
| I | Feyenoord | - | IF Elfsborg | 5:0 (3:0) | ||
| V | IF Elfsborg | - | Feyenoord | 3:1 (1:0) | ||
| I: 19.08.2021 20:00 | V: 26.08.2021 19:00 | Campeones: Feyenoord | ||||
| I | Sivasspor | - | FC København | 1:2 (0:0) | ||
| V | FC København | - | Sivasspor | 5:0 (2:0) | ||
| I: 19.08.2021 20:00 | V: 26.08.2021 19:00 | Campeones: FC København | ||||
| I | FK Jablonec | - | MŠK Žilina | 5:1 (4:0) | ||
| V | MŠK Žilina | - | FK Jablonec | 0:3 (0:1) | ||
| I: 19.08.2021 20:00 | V: 26.08.2021 18:00 | Campeones: FK Jablonec | ||||
| I | Paços de Ferreira | - | Tottenham Hotspur | 1:0 (1:0) | ||
| V | Tottenham Hotspur | - | Paços de Ferreira | 3:0 (2:0) | ||
| I: 19.08.2021 20:30 | V: 26.08.2021 20:45 | Campeones: Tottenham Hotspur | ||||
| I | CD Santa Clara | - | Partizan | 2:1 (1:0) | ||
| V | Partizan | - | CD Santa Clara | 2:0 (2:0) | ||
| I: 19.08.2021 22:30 | V: 26.08.2021 21:00 | Campeones: Partizan | ||||
