The blues drew 1-1 last Tuesday, conceding a late goal to the home side which cancelled out Caroline Weir’s second half strike, and City will look to complete the job on home soil.
City will be in buoyant mood after an opening day 4-0 victory at Goodison Park, which saw debutants Vicky Losada and Bunny Shaw both on the scoresheet, with Olympic gold medalist Janine Beckie and skipper Steph Houghton also on the scoresheet.
Real, on the other hand, go into the match on the back of a 4-0 opening day loss at Levante on Sunday, and after the trip to City, they face a home derby against Atletico Madrid on Sunday.
The away goal rule in European competition has been axed, meaning City cannot rely on their goal in Madrid on Tuesday and must win the match in order to progress.
Ellen White and Georgia Stanway could be in contention after missing the first leg through injury. Both featured as second half substitutes in the win at Everton and manager Gareth Taylor may be prepared to give them both their first starts of the season.
Karina Benameur Taieb looks set to retain her place between the sticks, with first choice Ellie Roebuck still out with a calf injury, while Karen Bardsley is sill struggling with a hamstring problem.
The blues squad was stretched at Madrid, but could still have come away with a win. With key players returning and home advantage, City should get the result that will see them into the group stage.
Manchester City Women 3-0 Real Madrid Women.