Ciro Immobile is back to lead Lazio, but they are forced into changes in defence, while Simone Inzaghi returns to face his former club with Ivan Perisic alongside Edin Dzeko.
It kicks off at the Stadio Olimpico at 17.00 UK time (16.00 GMT).
This is a very special match for Inzaghi, who between his time as a player and then a coach spent over 20 years calling Lazio his home.
He is expected to receive a warm welcome from the Biancocelesti ultras, who largely blamed President Claudio Lotito for his departure.
Immobile is back after missing the Nations League with Italy due to injury, flanked by Pedro and Felipe Anderson, with Sergej Milinkovic-Savic, but Toma Basic is preferred to Luis Alberto in midfield.
Defender Francesco Acerbi begins his two-match ban for insulting the referee, although there is an appeal in progress, so Patric steps into the back four.
Inter have several familiar faces at the Stadio Olimpico, as Joaquin Correa left Lazio over the summer, while Edin Dzeko played for their arch-rivals Roma for many years.
The question Inzaghi had to answer was whether to risk Lautaro Martinez from the start, considering he only arrived back in Italy last night from international duty with Argentina.
Instead, Ivan Perisic is moved into a more advanced position.
Hakan Calhanoglu is not 100 per cent fit either, so Roberto Gagliardini steps into midfield.
Lazio: Reina; Marusic, Luiz Felipe, Patric, Hysaj; Milinkovic-Savic, Leiva, Basic; Felipe Anderson, Immobile, Pedro
Inter: Handanovic; Skriniar, De Vrij, Bastoni; Darmian, Barella, Brozovic, Gagliardini, Dimarco; Dzeko, Perisic
Ref: Irrati
C’mon Lazio!