Antonio Cassano, Alexandre Pato and Clarence Seedorf form a new trident attack as Milan travel to Javier Pastore's Palermo.
The kick-off at 19.45 UK time sees the Serie A leaders aim to break their Sicilian taboo, having lost their last three consecutive trips to the Stadio Barbera.
Zlatan Ibrahimovic is suspended, as his three-match ban for punching Bari's Marco Rossi in the ribs starts this weekend.
This means the first time an all-new trio of Cassano, Pato and Seedorf start together in attack, leaving Robinho on the bench.
Massimo Ambrosini, Andrea Pirlo and Pippo Inzaghi are injured with Kevin-Prince Boateng not 100 per cent fit.
Palermo are missing Mattia Cassani and the suspended Cesare Bovo, so must re-work the three-man defence.
Dorin Goian returns from a long-term injury to start with Giulio Migliaccio, who has made the move from midfield to the back three under Serse Cosmi.
Mauricio Pinilla was expected to partner Fabrizio Miccoli in attack, but in a surprising move the captain is left on the bench.
Instead, Josip Ilicic is given this new attacking role, having been initially dropped by new Coach Cosmi.
Palermo have lost five on the bounce, but hope to continue their impressive home record against Milan.
Palermo: Sirigu; Munoz, Goian, Migliaccio; Darmian, Bacinovic, Nocerino, Balzaretti; Pastore; Pinilla, Ilicic
Milan: Abbiati; Abate, Nesta, Thiago Silva, Jankulovski; Gattuso, Van Bommel, Flamini; Seedorf; Pato, Cassano