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| 1st(1st leg) | Royal Pari | - | Oriente Petrolero | 2:3 (1:1) | ||
| 2nd (2nd leg) | Oriente Petrolero | - | Royal Pari | 3:0 (0:0) | ||
| 1st(1st leg): 08/03/2022 22:15 | 2nd (2nd leg): 15/03/2022 22:15 | Winner: Oriente Petrolero | ||||
| 1st(1st leg) | Sol de América | - | General Caballero DJLM | 0:3 (0:1) | ||
| 2nd (2nd leg) | General Caballero DJLM | - | Sol de América | 2:1 (1:1) | ||
| 1st(1st leg): 08/03/2022 22:15 | 2nd (2nd leg): 15/03/2022 22:15 | Winner: General Caballero DJLM | ||||
| 1st(1st leg) | Estudiantes de Mérida | - | Metropolitanos FC | 0:2 (0:1) | ||
| 2nd (2nd leg) | Metropolitanos FC | - | Estudiantes de Mérida | 4:0 (1:0) | ||
| 1st(1st leg): 08/03/2022 22:15 | 2nd (2nd leg): 15/03/2022 22:15 | Winner: Metropolitanos FC | ||||
| 1st(1st leg) | Ñublense | - | Unión La Calera | 0:0 (0:0) | ||
| 2nd (2nd leg) | Unión La Calera | - | Ñublense | 2:1 (1:0) | ||
| 1st(1st leg): 09/03/2022 00:30 | 2nd (2nd leg): 16/03/2022 00:30 | Winner: Unión La Calera | ||||
| 1st(1st leg) | Cienciano | - | FBC Melgar | 1:1 (0:1) | ||
| 2nd (2nd leg) | FBC Melgar | - | Cienciano | 1:0 (1:0) | ||
| 1st(1st leg): 09/03/2022 00:30 | 2nd (2nd leg): 16/03/2022 00:30 | Winner: FBC Melgar | ||||
| 1st(1st leg) | Liverpool | - | River Plate | 0:1 (0:1) | ||
| 2nd (2nd leg) | River Plate | - | Liverpool | 2:0 (0:0) | ||
| 1st(1st leg): 09/03/2022 22:15 | 2nd (2nd leg): 16/03/2022 22:15 | Winner: River Plate | ||||
| 1st(1st leg) | Independiente Medellín | - | América de Cali | 2:1 (1:0) | ||
| 2nd (2nd leg) | América de Cali | - | Independiente Medellín | 1:3 (1:1, 2:1) pso | ||
| 1st(1st leg): 10/03/2022 00:30 | 2nd (2nd leg): 17/03/2022 00:30 | Winner: Independiente Medellín | ||||
| 1st(1st leg) | Mushuc Runa | - | LDU Quito | 0:2 (0:0) | ||
| 2nd (2nd leg) | LDU Quito | - | Mushuc Runa | 1:1 (1:0) | ||
| 1st(1st leg): 10/03/2022 00:30 | 2nd (2nd leg): 17/03/2022 00:30 | Winner: LDU Quito | ||||
| 1st(1st leg) | Ayacucho FC | - | Sport Boys | 2:0 (1:0) | ||
| 2nd (2nd leg) | Sport Boys | - | Ayacucho FC | 3:2 (2:0) | ||
| 1st(1st leg): 10/03/2022 00:30 | 2nd (2nd leg): 17/03/2022 00:30 | Winner: Ayacucho FC | ||||
| 1st(1st leg) | Unión Española | - | Antofagasta | 1:2 (1:2) | ||
| 2nd (2nd leg) | Antofagasta | - | Unión Española | 4:1 (0:0, 0:1) pso | ||
| 1st(1st leg): 10/03/2022 22:15 | 2nd (2nd leg): 17/03/2022 22:15 | Winner: Antofagasta | ||||
| 1st(1st leg) | Club Nacional | - | Guaireña FC | 0:1 (0:0) | ||
| 2nd (2nd leg) | Guaireña FC | - | Club Nacional | 0:0 (0:0) | ||
| 1st(1st leg): 10/03/2022 22:15 | 2nd (2nd leg): 17/03/2022 22:15 | Winner: Guaireña FC | ||||
| 1st(1st leg) | Hermanos Colmenarez | - | Deportivo La Guaira | 2:0 (1:0) | ||
| 2nd (2nd leg) | Deportivo La Guaira | - | Hermanos Colmenarez | 3:0 (2:0) | ||
| 1st(1st leg): 10/03/2022 22:15 | 2nd (2nd leg): 17/03/2022 22:15 | Winner: Deportivo La Guaira | ||||
| 1st(1st leg) | Jorge Wilstermann | - | CD Guabirá | 4:0 (2:0) | ||
| 2nd (2nd leg) | CD Guabirá | - | Jorge Wilstermann | 3:0 (1:0) | ||
| 1st(1st leg): 11/03/2022 00:30 | 2nd (2nd leg): 18/03/2022 00:30 | Winner: Jorge Wilstermann | ||||
| 1st(1st leg) | La Equidad | - | Atlético Junior | 0:0 (0:0) | ||
| 2nd (2nd leg) | Atlético Junior | - | La Equidad | 3:1 (2:1) | ||
| 1st(1st leg): 11/03/2022 00:30 | 2nd (2nd leg): 18/03/2022 00:30 | Winner: Atlético Junior | ||||
| 1st(1st leg) | Delfín SC | - | 9 de Octubre | 1:1 (0:1) | ||
| 2nd (2nd leg) | 9 de Octubre | - | Delfín SC | 2:0 (2:0) | ||
| 1st(1st leg): 11/03/2022 00:30 | 2nd (2nd leg): 18/03/2022 00:30 | Winner: 9 de Octubre | ||||
| 1st(1st leg) | Montevideo Wanderers | - | Cerro Largo | 2:1 (0:0) | ||
| 2nd (2nd leg) | Cerro Largo | - | Montevideo Wanderers | 0:1 (0:0) | ||
| 1st(1st leg): 11/03/2022 00:30 | 2nd (2nd leg): 18/03/2022 00:30 | Winner: Montevideo Wanderers | ||||
