The tie is in the balance following a 0-0 stalemate at the Stadio Olimpico in Februarys first leg, with Milan boss Gennaro Gattuso probably coming away the happiest of the two managers.
The sides met at the San Siro just last weekend in Serie A and it was Milan who edged that cagey contest thanks to a late second-half penalty, converted by midfielder Franck Kessie.
Both Milan and Lazio were frustrated by their league fixtures on Saturday, as Milan were forced to settle for a point after a late Parma equaliser, while Lazio fell to a 2-1 home defeat to the leagues bottom side Chievo.
Where to Watch
When Is Kick Off?
Wednesday 24 April
What Time Is Kick Off?
Where Is It Played?
TV Channel/Live Stream?
BT Sport 2
Milan goalkeeper Gianluigi Donnarumma returned to the Milan lineup for Saturdays draw against Parma after recovering from a strain, with Lucas Paqueta fit enough to be named among the substitutes.
Midfielder Giacomo Bonaventura is still sidelined with a knee injury and will miss the rest of the season.
Lazio midfielder Sergej Milinkovic-Savic was sent off against Chievo for a kick off the ball but red cards in Serie A dont carry over to Coppa Italia fixtures, meaning the Serbian is available to play.
Defender Stefan Radu is, however, suspended for this one after being sent off in the previous round against Inter. Jordan Lukaku and Valon Berisha are both sidelined until the summer.
Donnarumma; Conti, Zapata, Romagnoli, Rodriguez; Kessie, Bakayoko, Calhanoglu; Suso, Piatek, Borini
Strakosha; Patric, Felipe, Acerbi; Romulo, Milinkovic-Savic, Lucas, Alberto, Lulic; Caicedo, Immobile
Head to Head Record
Milan have won this fixture significantly more often than they have lost, but a draw is a common result. The points have been shared 59 times in 152 Serie A meetings - including four of the previous five in all competitions.
Last time out, Wednesdays hosts secured a 1-0 win over Lazio, who havent won at the San Siro since 2015 when current Milan midfielder Lucas Biglia netted the winner.
Gennaro Gattusos side have earned just one victory in their previous six matches, which included a dramatic 3-2 derby defeat to Inter in March.
The boss criticised his sides performance in Saturdays frustrating draw, citing a lack of desire to get on the ball as a factor.
Lazios disappointing defeat to Chievo was their third defeat in five games, as they sit in eighth place in Serie A.
Heres how each team has performed in their last five fixtures:
Parma 1-1 Milan (20/4)
Lazio 2-1 Chievo (20/4)
Milan 1-0 Lazio (13/4)
Lazio 2-0 Udinese (17/4)
Juventus 2-1 Milan (6/4)
Milan 1-0 Lazio (13/4)
Milan 1-1 Udinese (2/4)
Lazio 2-2 Sassuolo (7/4)
Sampdoria 1-0 Milan (30/3)
SPAL 1-0 Lazio (3/4)
If the last five fixtures are anything to go by, Wednesday nights clash is likely to be another cagey affair. But there has to be a winner on the night and Milans mentality under Gattuso may just see them over the line.
Prediction: Milan 2-1 Lazio