Forever linked by Diego Maradona, both clubs topped their domestic leagues last season; however, neither has put up much of a title defence or impressed in the group stage.
Match preview
Quarter-finalists last year, Napoli finished as Group C runners-up in the first phase of this season's Champions League, trailing in eight points behind Real Madrid, who they were beaten by both home and away.
Nonetheless, three wins from their other four fixtures - against Braga and Union Berlin - proved enough to progress to the knockout rounds, and the Serie A side will now attempt to topple Real's old foes Barcelona for the very first time, having failed to do so in three previous contests across the last five seasons.
Though Walter Mazzarri returned in November, the Partenopei remain a shadow of their former selves, and recent results have left them in danger of missing out on European qualification altogether: at this stage of the Scudetto-winning 2022-23 campaign, they had put 65 points on the board - some 19 more than Mazzarri's men have now.
Mazzarri may be unbeaten in his five previous Champions League home games, but Wednesday's game will be just the third he has overseen in the knockout stages, with the previous two coming in 2012, when Napoli lost 5-4 on aggregate to Chelsea in the last 16.
Only a late leveller from Cyril Ngonge spared the Italian champions' blushes last Saturday, with the Belgian's first strike since joining in January rescuing a point against Genoa. Just enough to keep them ninth in the table, it was only Napoli's third goal in five matches - highlighting their impotency without last term's Capocannoniere, Victor Osimhen.
As a minor consolation, that draw preserved the Partenopei's unbeaten streak on home soil, as they have not lost any of their last five league fixtures at Stadio Maradona. In addition, defeat to Real Madrid earlier this season was Napoli's sole loss in 16 Champions League home games, of which they have won 10.
However, the Campanian club have never before beaten Barcelona, to whom they lost in the last 16 four years ago, when exiting Europe's top competition 4-2 on aggregate.
In fact, Barcelona also won 4-2 in their most recent 'Maradona derby', which came in the playoff round of the 2021-22 Europa League. History, then, is on their side this week.
Back in the Champions League's elimination phase for the first time in three years, the Blaugrana finished first in Group H, pipping Porto on head-to-head record after the pair both posted 12 points from six matches: a 5-0 crushing of Antwerp was followed by wins over the Portuguese side and Shakhtar Donetsk, but Barca then lost two of the next three.
Such inconsistency has characterised the Catalan club's season, and they are not only off the pace in La Liga's title race but also out of the Copa del Rey, and head coach Xavi has announced he will leave at the campaign's conclusion - if he is not removed any earlier.
Following last year's Spanish title win, third-placed Barcelona have put up a fairly dismal defence, but they do remain unbeaten away from home in La Liga, winning seven and drawing five on the road to date.
Last time out, at Balaidos, Robert Lewandowski's brace took him on to 50 goals for the club from 79 games, and the Polish striker's last-gasp winner again bailed Barca out of a tight spot: they have won 24 points this term via goals scored in the final 15 minutes or during stoppage time.
Xavi's side have also found the net at least once in each of their last 20 matches, but they have kept only three clean sheets in that time. That is one of several concerns for the five-time European champions, who are ultimately seeking a third European triumph at Wembley Stadium in June's final.
In contrast to their away form in domestic competition, Barcelona will head to Italy having won only one in 10 on their travels in the Champions League knockout stages over recent years, scoring just four goals and firing blanks in six.
Napoli Champions League form:
W
L
W
D
L
W
Napoli form (all competitions):
W
L
D
W
L
D
Barcelona Champions League form:
W
W
W
L
W
L
Barcelona form (all competitions):
L
L
W
W
D
W
Team News
Victor Osimhen started all seven games as Nigeria reached the recent Africa Cup of Nations final, and following a brief break to recover from his exertions in Ivory Coast, Napoli's main marksman is now back at Walter Mazzarri's disposal.
Osimhen should immediately replace misfiring striker Giovanni Simeone, and with Juan Jesus returning after Serie A suspension, the hosts have a fully available squad to choose from.
Pasquale Mazzocchi, Cyril Ngonge and Hamed Traore were all added to the Partenopei's UEFA list after the group stage, but Piotr Zielinski - who is set to leave on a free transfer this summer - has been omitted.
Meanwhile, Barcelona must do without Alejandro Balde, Gavi, Marcos Alonso, Sergi Roberto and Ferran Torres through injury, while Joao Felix remains doubtful due to an ankle problem.
The Blaugrana's main addition in January, Vitor Roque, could make his Champions League debut, and fellow young gun Lamine Yamal will be aiming to become the first 16-year-old to score in the competition.
Both could feature alongside Robert Lewandowski, who is without a goal in four Champions League appearances but has netted in his last three league outings and is Barca's top scorer this season with 17 goals.
Napoli possible starting lineup:
Meret; Di Lorenzo, Rrahmani, Jesus, Rui; Anguissa, Lobotka, Cajuste; Politano, Osimhen, Kvaratskhelia
Barcelona possible starting lineup:
Ter Stegen; Kounde, Araujo, Martinez, Cancelo; De Jong, Gundogan, Pedri; Yamal, Lewandowski, Roque