Napoli are forced to reshuffle without injured Victor Osimhen, so Giacomo Raspadori leads the attack with Kvicha Kvaratskhelia against a Spezia side that won here last season.
It kicks off at the Stadio Diego Armando Maradona at 14.00 UK time (13.00 GMT).
The Partenopei are brimming with confidence after thrashing Liverpool 4-1 here in the Champions League, but at the same time lost Osimhen for a month with a thigh injury.
Diego Demme is also on the treatment table, so Raspadori steps in to lead the attack with Matteo Politano and Serie A Player of the Month Kvaratskhelia.
Spezia famously won here last season with a smash and grab counter-attack and held both Sassuolo and Bologna to 2-2 draws following an opening round victory over Empoli.
There remains a lengthy absentee list, including Daniele Verde, Albin Ekdal, Daniel Maldini, Kelvin Amian and Salva Ferrer.
Wales international Ethan Ampadu is ready for his debut after a deadline day loan with option to buy move from Chelsea.
Napoli: Meret; Di Lorenzo, Rrahmani, Juan Jesus, Mario Rui; Anguissa, Ndombele, Elmas; Politano, Raspadori, Kvaratskhelia
Spezia: Dragowski; Ampadu, Kiwior, Nikolaou; Holm, Agudelo, Bourabia, Bastoni, Reca; Gyasi, Nzola