Man Utd v Real Betis (20:00 GMT)
Manuel Pellegrini won three of his six meetings with United as City boss, including a 3-0 triumph at Old Trafford in 2014.
His Betis side, who are fifth in La Liga, topped their Europa League group, while United reached the last 16 by beating Barcelona 4-3 on aggregate in the play-off round.
United's last five European campaigns have ended with defeat to Spanish opposition - and they also lost to Real Sociedad in September in the group stage.
"I cannot know what they think but if Real Sociedad can do it, we can beat Manchester United also," said Pellegrini.