The Women's Super League side are sitting in pole position with a perfect record, while the Catalan giants are three points adrift in second place.
Match preview
Barcelona are hoping to retain their UWCL crown after winning the top prize in European football in three of the last four seasons.
Their bid to win a fourth UWCL trophy got off to a rocky start as they fell to a 2-0 away defeat against Man City on matchday one.
However, they quickly got their campaign up and running with 7-0 and 9-0 home wins over Hammarby and St Polten respectively.
Pere Romeu's side went on to claim a 4-1 away win over St Polten in Austria, before they experienced more success in last week's trip to Sweden, with Ewa Pajor netting a brace in a 3-0 victory over Hammarby, keeping Barcelona in the hunt to secure top spot in Group D.
The Liga F champions know they have to beat Man City by a two-goal margin if they are to leapfrog their English opponents into first place.
They will certainly fancy their chances of claiming all three points after winning each of their last 12 competitive games since losing to Man City in the reverse fixture.
Man City have been flawless in their first-ever UWCL group-stage appearance, having taken maximum points from each of their five matches.
They began the main draw with a statement 2-0 home win over Barcelona, courtesy of goals from Naomi Layzell and Bunny Shaw.
Gareth Taylor's side then showed great character to come from 2-1 down to beat St Polten 3-2, before they recorded back-to-back European victories over Hammarby.
Man City enjoyed more success in last week's home clash against St Polten, with Lily Murphy and Kerstin Casparij finding the net in a 2-0 victory to ensure the Citizens will enter matchday six as one of three teams with a 100% record in this season's group stage.
Their perfect record will come under threat in Wednesday's fixture, especially as an injury-hit Man City side will be in a downbeat mood following a surprise 2-1 defeat in Sunday's WSL clash against Everton, leaving them six points adrift of WSL leaders Chelsea.
They will have to pick themselves up for a trip to Barcelona, knowing that a draw or a defeat by a one-goal margin will be enough to secure top spot, although they would love nothing more than to claim their first-ever win in Spain in European competition.
Barcelona Women Women's Champions League form:
L
W
W
W
W
Barcelona Women form (all competitions):
W
L
W
W
W
W
Manchester City Women Women's Champions League form:
W
W
W
W
W
W
Manchester City Women form (all competitions):
W
L
W
W
W
L
Team News
Barcelona are unable to call upon Martina Fernandez due to a knee issue, while Ellie Roebuck and Keira Walsh are doubts after missing Sunday's win over Valencia due to illness.
Caroline Graham Hansen will have to be assessed after her substitute appearance against Valencia was cut short due to an injury issue.
Alexia Putellas has missed the last four matches due to injury, but the two-time Ballon d'Or winner could return to the squad for Wednesday's UWCL fixture.
As for the visitors, they are unable to call upon a number of key players, including Lauren Hemp, Vivianne Miedema and Shaw.
Defender Alex Greenwood is set to miss a second straight game after picking up an injury in last week's UWCL win over St Polten.
The visitors are also without Sandy MacIver and Risa Shimizu, while it remains to be seen whether Layzell will be ready to feature in the matchday squad.
Barcelona Women possible starting lineup:
Coll; Batlle, Paredes, Leon, Rolfo; Bonmati, Guijarro, Pina; Nazareth, Brugts, Pajor
Manchester City Women possible starting lineup:
Yamashita; Casparij, Aleixandri, Kennedy, Ouahabi; Roord, Hasegawa, Blindkiled; Park, Fujino, Fowler
We say: Barcelona Women 3-1 Manchester City Women
Man City may have won all five of their group games, but they will travel to Barcelona without a number of key players, and we think their depleted squad could find it tough going against the European champions.
Written by
Ben Sully