After opening victories - Brugge winning 2-1 away at Zenit St Petersburg, while Lazio completed an impressive defeat of Borussia Dortmund in Rome - a second win would put either side in the driver's seat, with last-16 qualification becoming ever more tangible.
The hosts' fine victory in Russia last week - earned by virtue of a stoppage time goal from Charles De Ketelaere - was just their second win in 21 Champions League matches and the first time since 1992 that they had won their opening Champions League fixture.
Philippe Clement's side, who claimed their 16th Belgian league title in 2019-20 and third in the last five seasons, have had a mixed start to their domestic defence, however.
Having lost two of their first three league games this season, they then went on to win five in a row, scoring 17 goals and conceding only three in the process. They have dropped points either side of their European exploits though - drawing 1-1 at Standard Liege then surprisingly going down 2-1 at OH Leuven on Saturday.
The Blauw-Zwart certainly do not lack confidence in front of goal, though, as they are the leading scorers in the Belgian top flight this season, with 23 goals. Top scorers Krepin Diatta and Hans Vanaken have five each in the league and both featured prominently in the Zenit triumph.
Wednesday's clash with Lazio now provides Clement's charges with real hope of taking a foothold in a well-balanced Group F. Though Brugge are in the group stage for a third year in a row - the first time they have achieved such a feat - they have never progressed to the knockout rounds in eight attempts.
In fact, they have won none of their last 10 home matches in the group stage, losing six. Their record against Italian sides will do little to inspire confidence, too, as they have failed to score in their last four games and are without a win in their last nine matches versus sides from the peninsula.
Lazio's similarly meagre recent record is also cause for concern. Though the Biancocelesti's sixth Champions League campaign began with that excellent win over hotly-tipped Dortmund, last week's was only Lazio's second victory in their last 12 Champions League games.
Simone Inzaghi's men have lost their last five European away fixtures, including several in a not especially challenging Europa League group last year.
Like their hosts, Lazio have had a varied start to the new term, as their post-lockdown inconsistency continues. Having won none of their previous three Serie A matches, including three-goal defeats to both Atalanta and Sampdoria, Saturday's 2-1 success at home to Bologna came as a huge relief.
Their coach acknowledged after the game that his task is set to be much more difficult this season, as they traverse the Champions League group stage amid a packed fixture list.
Squad rotation will be "fundamental" stated Inzaghi, though Ciro Immobile - who scored 36 Serie A goals last season and got the first against Dortmund, before again scoring against Bologna - is one player who is simply indispensable. However, reports from training on Tuesday suggested that Immobile is one of several players affected by a pre-match COVID-19 outbreak.
Club Brugge Champions League form: W
Club Brugge form (all competitions): WWWDWL
Lazio Champions League form: W
Lazio form (all competitions): WLDLWW
In a major boost for the home side, Champions League stalwart Simon Mignolet, defender Odilon Kossounou and Czech forward Michael Krmencik, who all tested positive for COVID-19 a week ago, have now re-tested negative and have been back in training since Sunday morning.
Coach Clement employed a much-changed 3-5-2 in the weekend defeat to OH Leuven, after utilising a flexible 4-3-3 against Zenit. Rested striker Emmanuel Dennis will return to the starting XI, with young Senegalese striker Youssouph Badji dropping out.
Luis Alberto, Andreas Pereira, Lucas Leiva, Manuel Lazzari, Danilo Cataldi, Luiz Felipe and Thomas Strakosha are the Lazio players named alongside star striker man Immobile as being affected by the latest virus outbreak.
Experienced defender Stefan Radu has missed Lazio's last two games due to an injury to his right thigh and midfielder Sergej Milinkovic-Savic suffered a knock against Dortmund but may be ready for Wednesday night. Veteran wing-back Senad Lulic is still out of action though.
Club Brugge possible starting lineup:
Mignolet; Mata, Mechele, Ricca, Sobol; Vormer, Rits, Vanaken; Diatta, Dennis, De Ketelaere
Lazio possible starting lineup:
Reina; Patric, Hoedt, Acerbi; Marusic, Milinkovic-Savic, Parolo, Akpa Akpro, Fares; Caicedo, Correa
We say: Club Brugge 1-2 Lazio
Neither side has excelled at this level in recent history, so it was something of a surprise to see both sitting top of Group F after opening night victories.
As Lazio look for three wins on the spin, the guile of their experienced front line can defy a pre-match virus outbreak to continue their upswing in form - and prolong Brugge's terrible record against Italian teams.