Barca and Inter have seized the early initiative in Group B, and the winners of this seventh-ever meeting between the sides will take a giant step towards the last 16.
Lionel Messi netted a hat-trick in the first of those victories and then pulled the strings throughout at Wembley Stadium as Barca maintained their perfect start in Group B.
Devoid of their main creative talent for the next few weeks, however, with a fractured arm keeping Messi on the sidelines during a run of key games at home and on the continent, Barca's other star names must now step up.
Next weekend's La Liga showdown with Real Madrid can wait for now, as the Catalan giants are not quite over the line yet in Europe, knowing that defeat to Inter will give Spurs and PSV - who face off on the same night - a big chance to close the gap.
Losing games on home soil is not something that Barca tend to do in the Champions League, though, having gone 27 matches since last doing so in a run stretching back to September 2013.
Barca have won all of their home games in the group stage across the last five editions of the competition, in fact, while their quarter-final loss to Roma in April is their only defeat home or away in 12 Euro outings.
Ernesto Valverde's men did recently go four matches without victory in La Liga, however, dropping points to Girona and Athletic Bilbao here, as well as Leganes and Valencia on their travels, so hope is not lost for in-form Inter.
Saturday's 4-2 victory over Sevilla was a welcome boost for Barca, who are rightly considered many people's favourites to go all the way in the Champions League this time around following three quarter-final exits in a row.
Recent form in Champions League: WW
Recent form (all competitions): DLDWDW
Like Wednesday night's opponents Barca, Inter have also started their European campaign in style thanks to victories against Tottenham and PSV over the past five weeks.
The Nerazzurri did not exactly do things the easy way in either game, though, as they had to recover from a goal down against Spurs and likewise against PSV in their most recent outing.
Mauro Icardi and Matias Vecino were the heroes in that opening fixture, finding the net with quickfire goals in the final five minutes to get Inter off to a dream start, which they followed up with a comeback win at the Philips Stadion.
Late goals seem to come naturally to Luciano Spalletti's men, as they also found a way through in added time to pick up a massive 1-0 victory over arch-rivals AC Milan at San Siro on Sunday - Icardi again proving the difference with his sixth goal in six games.
That win leaves Inter six points adrift of champions Juventus, who are on course for an eighth successive title triumph, but momentum is certainly on the Nerazzurri's side.
Seven wins in a row in all competitions ensures that Spalletti's charges head to Catalonia on a high, while going further back it is just one defeat in 10 - coming at home to newly-promoted Parma - since the end of August.
As well as challenging Juve domestically, leaving their mark on the European stage is also one of Inter's big targets for the season, having been absent from UEFA's premier competition since 2011-12.
After picking up their first European away win in eight attempts at PSV three weeks ago, Italy's most recent continental champions are now aiming to maintain their charge by sending out a big message at Camp Nou.
Recent form in Champions League: WW
Recent form (all competitions): WWWWWW
Valverde has a big call to make in attack following confirmation that Messi, so often the difference maker for Barca in such fixtures, is to miss a handful of matches.
Having started Saturday's win over Sevilla on the bench, Sergi Roberto is likely to replace Nelson Semedo in a like-for-like change at right-back, but other alterations - enforced or otherwise - are expected to be kept to a minimum.
Inter will be without one of their key men, meanwhile, as Radja Nainggolan - on the scoresheet in the 2-1 win against PSV - injured his ankle at the weekend.
Barcelona possible starting lineup:
Ter Stegen; Roberto, Pique, Lenglet, Alba; Rakitic, Busquets, Arthur; Dembele, Suarez, Coutinho
Inter Milan possible starting lineup:
Handanovic; Vrsaljko, De Vrij, Skriniar, Asamoah; Brozovic, Vecino; Perisic, Martinez, Politano; Icardi
Head To Head
Despite both boasting a rich history in European competitions, Barca and Inter have met on just six previous occasions, each coming in the last 15 years.
The Catalans took four points off their opponents in the 2002-03 group stage and likewise in 2009-10, before coming out second best later that season when meeting in the semi-finals.
Barca have won all three previous home matches against Inter, scoring six goals without conceding.
We say: Barcelona 1-0 Inter Milan
Inter Milan are in good form and boast a pretty formidable record at this stage of the Champions League, progressing into the knockout rounds in each of their last eight participations. The Italian visitors will be further boosted by the news that Barcelona forward Messi is absent for both matches over the next fortnight, but the bottom line is that the Spanish champions always tend to get the job done at Camp Nou on European nights, so we are backing a narrow home win.