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| U | FC Barcelona | - | SSC Napoli | 1:1 (0:1) | ||
| R | SSC Napoli | - | FC Barcelona | 2:4 (1:3) | ||
| U: 17.02.2022 18:45 | R: 24.02.2022 21:00 | Winnaars: FC Barcelona | ||||
| U | Zenit St. Petersburg | - | Real Betis | 2:3 (2:3) | ||
| R | Real Betis | - | Zenit St. Petersburg | 0:0 (0:0) | ||
| U: 17.02.2022 18:45 | R: 24.02.2022 21:00 | Winnaars: Real Betis | ||||
| U | Borussia Dortmund | - | Rangers FC | 2:4 (0:2) | ||
| R | Rangers FC | - | Borussia Dortmund | 2:2 (1:2) | ||
| U: 17.02.2022 18:45 | R: 24.02.2022 21:00 | Winnaars: Rangers FC | ||||
| U | FC Sheriff | - | Sporting Braga | 2:0 (1:0) | ||
| R | Sporting Braga | - | FC Sheriff | 3:2 (2:0, 2:0, 2:0) d.p. | ||
| U: 17.02.2022 18:45 | R: 24.02.2022 21:00 | Winnaars: Sporting Braga | ||||
| U | Sevilla FC | - | Dinamo Zagreb | 3:1 (3:1) | ||
| R | Dinamo Zagreb | - | Sevilla FC | 1:0 (0:0) | ||
| U: 17.02.2022 21:00 | R: 24.02.2022 18:45 | Winnaars: Sevilla FC | ||||
| U | Atalanta | - | Olympiakos | 2:1 (0:1) | ||
| R | Olympiakos | - | Atalanta | 0:3 (0:1) | ||
| U: 17.02.2022 21:00 | R: 24.02.2022 18:45 | Winnaars: Atalanta | ||||
| U | RB Leipzig | - | Real Sociedad | 2:2 (1:1) | ||
| R | Real Sociedad | - | RB Leipzig | 1:3 (0:1) | ||
| U: 17.02.2022 21:00 | R: 24.02.2022 18:45 | Winnaars: RB Leipzig | ||||
| U | FC Porto | - | Lazio Roma | 2:1 (1:1) | ||
| R | Lazio Roma | - | FC Porto | 2:2 (1:1) | ||
| U: 17.02.2022 21:00 | R: 24.02.2022 18:45 | Winnaars: FC Porto | ||||
