Lazio are forced to completely revamp with Joaquin Correa supported by Luis Alberto and Lucas Leiva, as Ciro Immobile and Felipe Caicedo are suspended, while Milan start Zlatan Ibrahimovic.
It kicks off at the Stadio Olimpico at 20.45 UK time (19.45 GMT).
If you fancy a punt, then check out the betting preview for Lazio-Milan on Eurotips.co.uk.
Simone Inzaghi has to scrap Plan A entirely for this showdown, as both Capocannoniere Immobile and his natural replacement Caicedo sit out bans.
Bobby Adekanye, Luiz Felipe and Adam Marusic are also injured, so the only available forward is Tucu Correa.
It’s a return to the old days, with Luis Alberto pushed into a more advanced role behind the lone striker, giving Sergej Milinkovic-Savic free rein to surge forward from midfield.
That’s even more true now that Lucas Leiva is not only back in the squad for the first time since knee surgery on April 4, but thrown straight into the starting XI.
Milan lost Samu Castillejo to a muscular injury during their 2-2 draw with SPAL midweek, a game they had been losing against 10 men until a last-gasp own goal.
Alexis Saelemaekers steps in with Giacomo Bonaventura and Hakan Calhanoglu, benching Lucas Paqueta, but the big news is that Ibrahimovic is in the starting XI.
The Swede made his first appearance since the lockdown as a substitute against SPAL and now takes over from a tired-looking Ante Rebic.
Lazio: Strakosha; Patric, Acerbi, Radu; Lazzari, Milinkovic-Savic, Leiva, Parolo, Jony; Luis Alberto; Correa
Lazio bench: Proto, Guerrieri, Bastos, Vavro, Armini, Falbo, J Silva, J Lukaku, Cataldi, A Anderson, D Anderson, Adekanye
Milan: G Donnarumma; Conti, Kjaer, Romagnoli, Theo Hernandez; Kessie, Bennacer; Saelemaekers, Bonaventura, Calhanoglu; Ibrahimovic
Milan bench: Begovic, A Donnarumma, Calabria, Gabbia, Laxalt, Biglia, Paqueta, Brescianini, Krunic, D Maldini, Leao, Rebic
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