Napoli look to Edinson Cavani, Ezequiel Lavezzi and Marek Hamsik, but Villarreal surprisingly start Giuseppe Rossi.
The 19.45 UK time kick-off will be the first Champions League/European Cup game played at the San Paolo in 21 years.
The ‘Three Tenors' lead the way, though Walter Mazzarri must do without the injured Christian Maggio, Marco Donadel, Blerim Dzemaili and Miguel Angel Britos.
There were reports Hugo Campagnaro would be rested, but the classic three-man defence is in its entirety.
Villarreal had suggested Rossi would not even be on the bench with his agent stating it was “impossible” for him to recover in time for the game, but the Italian international is in the starting XI.
Absent are Marco Ruben and the suspended Borja Valero.
Napoli: De Sanctis; Campagnaro, Cannavaro, Aronica; Zuniga, Inler, Gargano, Dossena; Hamsik, Lavezzi; Cavani
Napoli bench: Rosati, Fideleff, Fernandez, Mascara, Santana, Grava, Pandev
Villarreal: Diego Lopez; Zapata, Musacchio, Gonzalo Rodriguez, Català; Cani, Senna, Bruno Soriano, De Guzman; Nilmar; Rossi
Villarreal bench: Cesar Sanchez, Mario Gaspar, Oriol, Marchena, Perez, Camunas, Mubarak