Ciro Immobile leads the way for Lazio with a revamped midfield, but Atalanta are forced to completely transform after a COVID outbreak.
It kicks off at the Stadio Olimpico at 19.45 GMT.
This is a head-to-head for a top four finish and also has history behind it, as La Dea are still steaming after a controversial Coppa Italia Final defeat to Lazio.
The hosts have Danilo Cataldi suspended, Pedro, Stefan Radu and Francesco Acerbi injured, plus Jean-Daniel Akpa-Akpro at the Africa Cup of Nations.
Lucas Leiva therefore gets his first Serie A start since October, with Mattia Zaccagni shaking off an ankle sprain to join Ciro Immobile and Felipe Anderson upfront.
Duvan Zapata and Robin Gosens are injured, with Luis Muriel, Teun Koopmeiners, Josip Ilicic, Ruslan Malinovskyi, Mario Pasalic and Hans Hateboer unavailable.
Lazio: Strakosha; Hysaj, Luiz Felipe, Patric, Marusic; Milinkovic-Savic, Leiva, Luis Alberto; Felipe Anderson, Immobile, Zaccagni
Lazio bench: Reina, Adamonis, Romero, Vavro, Jony, Raul Moro, Andre Anderson, Lazzari, Floriani Mussolini, Bertini, Basic, Muriqi
Atalanta: Musso; Djimsiti, Demiral, Palomino, Zappacosta; Scalvini, Freuler, Pezzella; Miranchuk, Pessina; Piccoli
Atalanta bench: Rossi, Sportiello, Toloi, Maehle, Oliveri, Pananda