Inter debut Ivan Perisic and Felipe Melo with Gary Medel in defence, as Milan revamp behind Carlos Bacca and Luiz Adriano.
It’s the Derby della Madonnina and it kicks off at a packed San Siro at 19.45 UK time (18.45 GMT).
Old friends Roberto Mancini and Sinisa Mihajlovic said they will be “enemies for 90 minutes” tonight on the touchline in their first Milan Derby.
Mancio makes big changes to his side and a victory would mean Inter are the only side with a 100 per cent record after three rounds.
Deadline day signings Perisic and Melo are thrown straight in at the deep end for their debuts.
Joao Miranda is out injured, but Medel is moved to central defence – a role he already plays for Chile – rather than risk starting former captain Andrea Ranocchia.
Stevan Jovetic is the man to watch, having so far scored all three of Inter’s goals this season, but Mauro Icardi returns from a hamstring injury to complete the trident.
Alex Telles is benched in favour of Juan Jesus at left-back.
Milan are also transformed after Mihajlovic said “we can’t do much worse” than performances against Fiorentina and Empoli.
Andrea Bertolacci joined Jeremy Menez, Luca Antonelli and M’Baye Niang on the treatment table, so Montolivo gets his first start of the season with Juraj Kucka.
Keisuke Honda is picked ahead of Giacomo Bonaventura in the trequartista role behind strikers Bacca and Luiz Adriano.
Rodrigo Ely returns from suspension, but Cristian Zapata is preferred at the back.
Inter: Handanovic; Santon, Medel, Murillo, Jesus; Guarin, Melo, Kondogbia; Perisic, Icardi, Jovetic
Inter bench: Carrizo, Telles, Montoya, Ranocchia, D'Ambrosio, Nagatomo, Gnoukouri, Brozovic, Palacio, Biabiany, Ljajic, Manaj
Milan: Diego Lopez; Abate, Zapata, Romagnoli, De Sciglio; Kucka, Montolivo, Bonaventura; Honda; Luiz Adriano, Bacca
Milan bench: Abbiati, Donnarumma, Alex, Calabria, Rodrigo Ely, Mexes, Poli, De Jong, Nocerino, Suso, Balotelli, Cerci.