The Slovakian international, who has starred for the Naples-based outfit since 2007, started his career with Slovan, for whom he made six appearances before he was transferred to Brescia at the age of 17 a decade ago.
Hamsik is expected to start against his former club, along with the likes of Gonzalo Higuain, Lorenzo Insigne and Jonathan de Guzman, as Rafael Benitez's men look to put aside their inconsistent Serie A form.
Meanwhile, the Slovan starting lineup is likely to include Guinea midfielder Seydouba Soumah, who has scored five goals in eight Super Liga outings this season.
Of the four Italian clubs that have previously made the trip to the Slovakian capital, only AC Milan in 1992 recorded a victory thanks to a goal from Paolo Maldini. Roma were held to a 1-1 draw, while Inter Milan and Torino suffered defeats. As for Napoli, they have never faced a Slovakian club.
On matchday one, Slovan were heavily beaten 5-0 by Young Boys, while Napoli defeated Sparta Prague 3-1.
Possible starting lineups
Slovan: Pernis; Cikos, Kolcak, Ninaj, Jablonsky; Milinkovic, Grendel, Peltier, Kubik, Soumah; Stefanik
Napoli: Rafael; Britos, Albiol, Koulibaly, Zuniga; De Guzman, Gargano; Callejon, Hamsik, Insigne; Higuain
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