Defiant Inter Milan host champions Juventus for their first major home game of the season while Serie A leaders Napoli look to tighten their grip against visitors Atalanta.
AC Milan, the only major team in Italy's top flight to drop points so far, visit Torino in Saturday's other fixture hoping the recent signing of Brazilian Kaka pays dividends.
Three years after an historic treble of league, Cup and Champions League trophies, Inter finished a lowly ninth last season and are desperate to make amends under new coach Walter Mazzarri.
So far, they have recorded comparatively easy wins over Genoa and Catania and Juventus 'keeper Gianluigi Buffon believes Inter's absence from Cup or European competition makes them bona fide title challengers.
"We have great respect for Inter," said Buffon, who collected a record-equalling 136th cap for Italy in a 2-1 win over the Czech Republic in midweek.
"They're a strong team who want to show what they can do, they have one of the best coaches in the business and players who, when they're on their game, should be highly respected.
"And the fact they are not involved in any Cup competitions will only add to their status as potential title challengers this season."
While a number of Juventus players were on international duty nearby in in midweek, when Italy stamped their ticket for the 2014 World Cup with two qualifiers to spare, Inter also had a number of stars in action.
Several of Mazzarri's side are from south America and, thankfully for him, all returned from their respective midweek games unscathed.
The big news for Inter fans, however, is the likely selection of Argentine striker Diego Milito, who appears to be nearing full fitness following his recovery from knee surgery and a seven-month injury lay-off.
Milito is likely to start on the bench and may be lucky to be given a cameo appearance in such a high-stakes fixture, but his return will lift morale.
Ahead of the 'Derby d'Italia', Juventus wing-back Stephan Lichsteiner backed Inter's title credentials but says Juve have no intention of sitting back.
"We know Inter will be fired up and determined, but so are we," said the Swiss international.
A win or draw would put Inter top ahead of Saturday's late games when Mazzarri's former club, Napoli, host Atalanta and Milan visit a Torino side looking to make amends for last week's 2-0 defeat at Atalanta.
Napoli coach Rafael Benitez scored a minor coup when he signed Argentine Gonzalo Higuain to replace Uruguayan Edinson Cavani, Serie A's top scorer last season who signed for Paris Saint Germain.
But amid the debate over hefty transfer fees, Benitez believes he has one of the world's best scoring midfielders in Slovakian Marek Hamsik, who has scored four goals in two games to put Napoli top ahead of Inter on goal difference.
A week after Real Madrid paid Tottenham £80 million ($124 million, 94 million euros) for Welshman Gareth Bale, Benitez believes Hamsik is worth even more.
"Is Bale worth the 100 million euros Real Madrid paid for him? If so, then I'd say you can't put a price on Hamsik -- and he is not for sale," the Spaniard said in an interview with Mediaset.
Milan are missing defenders Ignazio Abate and Mattia De Sciglio for the visit to Turin and although Kaka is battling his way back to match fitness he is expected to make an appearance on Saturday.
Fixtures (times GMT)
Inter v Juventus (1600), Napoli v Atalanta, Torino v Milan (both 1845)
Fiorentina v Cagliari (1030), Verona v Sassuolo, Lazio v Chievo, Livorno v Catania, Udinese v Bologna (all 1300), Sampdoria v Genoa (1845)
Parma v Roma (both 1845)