Napoli must choose between Giacomo Raspadori and Giovanni Simeone upfront, while Milan have midfield doubts with Mike Maignan and Theo Hernandez back from suspension.
It kicks off at the Stadio Diego Armando Maradona on Sunday at 19.45 GMT.
This is a head-to-head for the Scudetto and a game that was played last season in both Serie A and the Champions League quarter-final.
Napoli are missing Victor Osimhen after an injury on international duty, so coach Rudi Garcia has to choose between Raspadori and Simeone upfront.
The Italian is the favourite, having started against both Verona and Union Berlin.
Andre Frank Zambo Anguissa is back on the bench, but not 100 per cent fit, so Jens Cajuste or Eljif Elmas are likely to take over in midfield.
Milan are without Ruben Loftus-Cheek, Samuel Chukwueze, Ismael Bennacer, Mattia Caldara, Marco Sportiello and the suspended Malick Thiaw.
Maignan and Theo Hernandez return after sitting out bans against Juventus, while Luka Jovic and Noah Okafor are only fit for the bench.
The main doubts are in defence between Pierre Kalulu and Simon Kjaer, while Rade Krunic and Yacine Adli are challenging for the midfield spot.
Probable line-ups
Napoli (4-3-3): Meret; Di Lorenzo, Rrhamani, Natan, Mario Rui; Cajuste, Lobotka, Zielinski; Politano, Raspadori, Kvaratskhelia
Milan (4-3-3): Maignan; Calabria, Kalulu, Tomori, Theo Hernandez; Reijnders, Krunic, Musah; Pulisic, Giroud, Leao
How Krunic can challenge Adli for a spot in the starting eleven only Pioli knows. Bottom tier coach.