Alex Meret makes his debut in a Napoli jersey and Faouzi Ghoulam returns after more than a year, as Carlo Ancelotti makes numerous changes for a potentially tricky game against Frosinone.
It kicks off at the Stadio San Paolo at 14.00 GMT.
As Juventus beat Inter 1-0 last night with a Mario Mandzukic diving header, this presents a big opportunity for the Partenopei.
A win would allow Napoli to stay within eight points of the leaders, but also open up a six-point gap from Inter in third.
However, the vast squad rotation confirms Ancelotti has his sights set firmly on Champions League progress and next week’s showdown with Liverpool at Anfield.
Raul Albiol and Simone Verdi are out injured, so Sebastiano Luperto partners Kalidou Koulibaly in the centre of defence.
The biggest change is in goal, where ex-Udinese and SPAL shot-stopper Meret finally makes his Napoli debut.
Meret broke a bone in his arm during his second training session and then had a recurring shoulder issue, but is at last ready for his bow.
It is Ghoulam’s first appearance since he ruptured his anterior cruciate ligament in November 2017 against Manchester City, as the full-back is thrown straight into the starting XI.
Arkadiusz Milik scored a spectacular late winner against Atalanta on Monday evening as a substitute and earns a starting spot alongside Lorenzo Insigne, allowing Dries Mertens to rest ahead of Anfield.
Frosinone are not to be underestimated, as while they had a disastrous start to the season, Coach Moreno Longo has recently been able to steer them back on track.
Although the 3-0 victory away to SPAL on October 28 is the only high point, they have lost just one of their last six Serie A games and that was at San Siro with Inter.
They held Empoli, Parma, Fiorentina and Cagliari to stalemates.
Considering Napoli were held by bottom of the table Chievo a couple of weeks ago, the potential is certainly there for another upset.
Camillo Ciano and Raffaele Maiello both spent time in the Napoli youth academy and are particularly eager to impress at the San Paolo, especially after shaking off injury.
Daniel Ciofani is on the bench, as Joel Campbell and Andrea Pinamonti form a new partnership.
Federico Dionisi, Emil Hallfredsson and Luca Paganini are on the treatment table.
Napoli: Meret; Hysaj, Luperto, Koulibaly, Ghoulam; Ounas, Allan, Hamsik, Zielinski; Milik, Insigne
Napoli bench: Ospina, Karnezis, Mario Rui, Maksimovic, Malcuit, Fabian Ruiz, Rog, Diawara, Younes, Mertens, Callejon
Frosinone: Sportiello; Goldaniga, Ariaudo, Capuano; Zampano, Chibsah, Maiello, Cassata, Beghetto; Campbell, Pinamonti
Frosinone bench: Bardi, Ghiglione, Molinaro, Vloet, D Ciofani, Soddimo, Perica, Sammarco, Brighenti, Salamon, Ciano, Crisetig
See the latest Serie A predictions and betting tips with Eurotips.co.uk