The Nerazzurri coach left Naples in the summer and he will be determined to show he has made the right decision, while Rafael Benitez will also have something to prove
The San Vincenzo native spent four years with the Partenopei before moving to San Siro during the summer and will make his return with four points and one league place separating the two sides.
Napoli have the advantage at present but have suffered inconsistent domestic form of late and Rafael Benitez will have something to prove following a short and unsuccessful stint at Inter after Jose Mourinho had turned them into treble winners in 2010.
While Sunday's hosts come into the game on the back of a 2-0 victory over Arsenal in the Champions League, they missed out on progression from the group stages and have won only twice in their last five top-flight outings.
After suffering back-to-back defeats against Juventus and Parma, Rafael Benitez's men overcame Lazio 4-2 at the Stadio Olimpico before dropping points against Udinese in a 3-3 draw.
That mixed form has seen last season's runners-up slip five points behind second-place Roma and eight off leaders Juventus, but defender Raul Albiol feels their meeting with Inter can provide a platform for Napoli to push on.
"We know that on Sunday we face an important game," the former Real Madrid centre-half told Radio Kiss Kiss.
"It will be a high-standard match. This year Napoli changed the formation, welcomed some new players and we are led by a new coach.
"We must work hard and continue to grow. We know we still need time to settle our new squad and there is always something that should be improved."
Inter, on the other hand, have been in fine form over recent weeks, avoiding defeat in their last eight Serie A matches, although they have struggled to convert their impressive performances into victories, drawing their last three games.
Rodrigo Palacio and Fredy Guarin have been impressive, each scoring twice in their last two league matches, and Inter are likely to need both at their best in order to arrest their poor record at Napoli.
Inter have only won once at the San Paolo in their last nine attempts, requiring penalties to secure victory in a Coppa Italia clash two years ago.
Neither side can move up the table even with a three-point haul, although Inter could slip a place if they drop points and Fiorentina beat Bologna at the Artemio Franchi.
Guarin is expected to shake off a knock suffered in training on Wednesday but Mauro Icardi (hernia), Diego Milito, Cristian Chivu and Walter Samuel are likely to miss out for Mazzarri's side.
Goalkeeper Pepe Reina and captain Marek Hamsik could return to bolster Benitez's squad after missing the win over Arsenal in midweek. But they could be without Juan Zuniga.