When the two Italian giants met at Stadio Maradona in the league this month, Milan emerged 4-0 winners, and they now take a one-goal lead with them down to Naples.
Match preview
They may be set to relieve Serie A's reigning champions of their Scudetto, leading Italy's top flight by some 14 points with just eight games left to play, but Napoli have failed to get the better of Milan in recent weeks and have a deficit to overturn if they are to reach the Champions League's final four.
Despite a typically fast start at San Siro, they were unable to take their chances in last Wednesday's first leg, and Ismael Bennacer's strike just before the break gave their Rossoneri rivals a slim lead ahead of this week's return in Campania. Late on, the dubious dismissal of Andre-Frank Zambo Anguissa for a second bookable offence only served to cap a frustrating night for the visitors.
Having suffered a shock four-goal league loss to Milan at the beginning of April, the fabled Stadio Maradona no longer seems such an impenetrable fortress, as not only have Napoli also lost to Lazio there recently, at the weekend they failed to break down a dogged Hellas Verona side battling against relegation.
Held to a goalless home draw by the Scaligeri on Saturday, perhaps the only positive note for Luciano Spalletti's men came when talismanic striker Victor Osimhen returned from injury as a second-half substitute - to much delight from the expectant home fans.
Even during a brief cameo, the Capocannoniere leader thumped a thunderous shot against the crossbar, but his teammates have now found the net just twice in their last four matches, which contrasts starkly with their previous output - for instance, Napoli are the Champions League's top scorers.
Indeed, they are unbeaten in their last 12 home matches in Europe's top club competition, winning each of their four fixtures at the Maradona this season and scoring at least three times on each occasion.
Despite an almost inevitable decline after such an accumulation of both goals and wins, Spalletti and co are still on course to clinch a first domestic title since 1990, but reaching the Champions League semi-finals would break new ground for one of Calcio's most famed clubs.
The last side to beat Napoli three times in one season was Lazio, way back in the 1994-95 campaign, but Milan will surely feel they have the Azzurri's number after back-to-back wins over them this month.
The Rossoneri have also taken maximum points from each of their last three league visits to Naples, so will not be intimidated by the warm southern welcome that awaits them on Tuesday.
Following a Mike Maignan-inspired success at San Siro last week - when they nullified their Neapolitan counterparts and a moment of magic from Brahim Diaz helped Bennacer to score - they are within touching distance of another semi-final place in a competition where they have a rich history.
Milan have ultimately come through 38 of 44 UEFA ties after winning the first leg at home, so history is certainly on their side as they seek to secure a potential last-four date with city rivals Inter next month - the Nerazzurri lead Benfica by two goals and are in the same half of the draw.
On Saturday, though, a much-changed XI continued a rough run of results in Serie A, with the victory over Napoli being Milan's only domestic success since February.
Over the intervening period, Pioli has seen his team toppled by both Udinese and Fiorentina, and held by Salernitana, Empoli, and now in-form Bologna. After falling behind within a minute at Stadio Dall'Ara, Tommaso Pobega's powerful strike salvaged a point which keeps them fourth in the table and just ahead of Inter.
For all their troubles during a dismal defence of their title - they sit 22 points adrift of Napoli in the Serie A standings - Milan consistently thrive in continental competition, and a sometimes shaky defence has not shipped a single goal in their last five Champions League matches.
Napoli Champions League form:
W
W
L
W
W
L
Napoli form (all competitions):
W
W
L
W
L
D
AC Milan Champions League form:
L
W
W
W
D
W
AC Milan form (all competitions):
D
L
W
D
W
D
Team News
Luciano Spalletti's hand will be forced into making at least two changes from the first leg, though a third may transform his team's hopes of overturning their one-goal deficit.
After Kim Min-jae was booked for dissent in the closing stages at San Siro, Napoli's defensive rock joins Andre-Frank Zambo Anguissa on the sidelines due to suspension, but the return of top scorer Victor Osimhen up front will certainly compensate.
Though the Nigeria international has now fully recovered from injury, his deputy Giovanni Simeone again misses out with a thigh problem; fellow forward Giacomo Raspadori should drop out of the starting XI.
In Anguissa's absence, either Eljif Elmas or Tanguy Ndombele will complete the hosts' midfield trio alongside Stanislav Lobotka and Piotr Zielinski. The latter has been involved in five goals from four home Champions League appearances this season; averaging a goal involvement every 49 minutes.
Milan, meanwhile, made 10 changes to their team on Saturday, as only Mike Maignan was retained and Stefano Pioli's second string were given an opportunity to impress.
Reverting to full strength, the visitors should be unchanged from last week's win on home soil, with Olivier Giroud leading the line; the veteran striker has been involved in six goals from nine European outings this season - the best tally for Milan since Zlatan Ibrahimovic in 2011-12.
The Swedish striker is both ineligible and injured so misses out on Tuesday, but Simon Kjaer, Sandro Tonali and Rafael Leao are among those set to feature again.
Only Real Madrid's Vinicius Junior has completed more dribbles than Leao (33) in the Champions League this term, and the Portuguese winger's tally represents the most by a Milan player since Kaka in 2004-05 (37).
Napoli possible starting lineup:
Meret; Di Lorenzo, Rrahmani, Jesus, Rui; Ndombele, Lobotka, Zielinski; Lozano, Osimhen, Kvaratskhelia
AC Milan possible starting lineup:
Maignan; Calabria, Kjaer, Tomori, Hernandez; Krunic, Tonali; Diaz, Bennacer, Leao; Giroud
We say: Napoli 1-1 AC Milan (AC Milan win 2-1 on aggregate)
While Napoli play the more thrilling football, Milan's pragmatism has served them well in this season's competition and could now carry them into the semi-finals.