Napoli bring in Giovanni Simeone for injured Victor Osimhen to partner Kvicha Kvaratskhelia, while Olivier Giroud and Rafael Leao lead a Milan return to their old tactics in this massive showdown.
It kicks off at the Stadio Diego Armando Maradona at 19.45 UK time (18.45 GMT).
This is the first of three meetings between the clubs, as they will also face off in the Champions League quarter-finals on April 12 and 18.
Osimhen hopes to be back for the first leg of that tie, but is out here after picking up a muscular injury on international duty with Nigeria.
Simeone therefore steps in with Kvaratskhelia and Matteo Politano, while Bartosz Bereszynski and Matias Olivera are also injured.
Milan make the trip without Zlatan Ibrahimovic, Junior Messias and Pierre Kalulu, but Giroud is available again after missing the 3-1 defeat to Udinese through suspension.
The race for the top four is tighter than ever and Stefano Pioli switches back to the 4-2-3-1 formation after experimenting a three-man defence for the last month.
That also means the return of Davide Calabria and Simon Kjaer, sending Malick Thiaw to the bench.
Napoli: Meret; Di Lorenzo, Rrahmani, Kim Min-jae, Mario Rui; Anguissa, Lobotka, Zielinski; Politano, Simeone, Kvaratskhelia
Milan: Maignan; Calabria, Kjaer, Tomori, Theo Hernandez; Tonali, Bennacer; Brahim Diaz, Krunic, Leao; Giroud
Player statistic
| 17' |  |
Rafael Leão (Assist: Brahim Díaz) | ||
| 25' | |
Brahim Díaz | ||
| 35' |  |
Olivier Giroud | ||
| Stanislav Lobotka | |
40' |
| 59' | |
Rafael Leão (Assist: Sandro Tonali) | ||
| 63' | |
Rade Krunic | ||
| 67' | |
Alexis Saelemaekers (Assist: Davide Calabria) |
Match statistic
