Gianluca Zambrotta is a shock starter with Kevin-Prince Boateng, Alexandre Pato and Robinho, while Inter unleash the four-man attack with Goran Pandev.
As only two points separate them at the top of the table, tonight's match is worth local rivalry, the leadership and probably also the Scudetto.
Even a draw could be decisive, as Napoli are ready to close in on the Milanese giants.
Zlatan Ibrahimovic is suspended, joining Andrea Pirlo, Massimo Ambrosini, Daniele Bonera, Pippo Inzaghi and Marek Jankulovski in the stands.
Coach Max Allegri made a surprise decision to throw in veteran Zambrotta at left-back, sending Luca Antonini to the bench.
Antonio Cassano is dropped due to poor form, so Boateng supports Pato and Robinho.
Inter are going with an all-attack approach in their 4-2-1-3 system with Wesley Sneijder supporting a trident.
Pandev is the extra man, joining Samuel Eto'o and Giampaolo Pazzini, so Dejan Stankovic is pushed on to the sidelines to make room.
At the back Lucio is suspended and Walter Samuel injured, but Andrea Ranocchia and Cristian Chivu both recovered from knocks to start.
The Stadio Giuseppe Meazza is completely sold out tonight with 80,018 tickets sold.
Milan: Abbiati; Abate, Nesta, Thiago Silva, Zambrotta; Gattuso, Van Bommel, Seedorf; Boateng; Pato, Robinho
Milan bench: 12 Amelia, 15 Papastathopoulos, 16 Flamini, 18 Emanuelson, 76 Yepes, 77 Antonini, 99 Cassano
Inter: Julio Cesar; Maicon, Ranocchia, Chivu, Zanetti; Thiago Motta, Cambiasso; Sneijder; Pandev, Eto'o, Pazzini
Inter bench: 12 Castellazzi, 2 Cordoba, 5 Stankovic, 14 Kharja, 22 Milito, 23 Materazzi, 55 Nagatomo