Lazio attempt to consolidate their top-two position in Champions League Group F as they welcome a Zenit side who are bottom of the section at the halfway stage - already four points adrift of Tuesday's opponents.
In the reverse fixture last time out, Aleksandr Erokhin's first-half goal looked set to give Zenit a first win of the campaign in their first ever fixture against the Rome club, but Biancocelesti super-sub Felipe Caicedo levelled with eight minutes remaining.
After snatching an added-time winner against Torino and that late equaliser at Zenit, veteran striker Caicedo struck in added time again to earn a 1-1 draw against Juventus - Lazio's third successive added-time goal in Serie A, following Ciro Immobile and Caicedo's strikes against Torino.
While the result in St Petersburg represented Zenit's first point in this season's competition, unbeaten Lazio are on five. The Italian club are handily poised, one point behind leaders Borussia Dortmund - whom they impressively turned over in their opening encounter - and one ahead of Club Brugge.
Simone Inzaghi's side went into the international break unbeaten in six games during a challenging period which saw the club overwhelmed by a string of positive virus tests under UEFA administration.
Players subsequently sent into self-isolation then rapidly re-emerged for Serie A action - following the club's private testing regime - before once again registering a positive test ahead of midweek Champions League action.
Now though, such controversy seems largely behind them, even if star midfielder Sergej Milinkovic-Savic became the latest Lazio player to contract COVID-19 - while on national duty with Serbia - and has entered a period of self-isolation.
At the weekend, Lazio comfortably beat Crotone on a rain-ruined pitch in what was at times a fairly farcical contest, where the ball often held up badly on the playing surface, with the returning Immobile joining club legend Giuseppe Signori on 107 goals for the Biancocelesti.
With a once-stretched squad finally approaching full strength, popular head coach Inzaghi will be targeting progress to the last 16 as a priority. If that is to be achieved, their historic record in Europe's premier competition must improve markedly.
The win against Dortmund was only Lazio's second in their last 14 Champions League matches, having lost six of those fixtures. Most recently, Inzaghi's men have lost eight of their last 13 European matches - winning just three - at Europa League level.
Disappointingly beaten 2-1 at home by Club Brugge on the opening night, Zenit then lost at Dortmund's Signal Iduna Park before getting their first point on the board against Tuesday's opponents last time out.
Just before the international period, captain and totemic frontman Artem Dzyuba was dropped by national team coach Stanislav Cherchesov in the wake of an obscene video scandal. Though manager Sergei Semak did choose to select the towering target man for the Russian Premier League clash with Krasnodar, centre-back Dejan Lovren assumed the captaincy with Dzyuba stripped of the armband in disgrace.
Several sections of the Zenit crowd - allowed to enter in reduced numbers in accordance with Russian health ministry guidelines - hurled abuse at their skipper and he missed a penalty on the stroke of half time, but then went on to score what was effectively the winner to a rapturous reception. Armband or no armband, their controversial striker will again be the focal point of their efforts at Stadio Olimpico.
Thanks, in part to Dzyuba's considerable input, Zenit claimed their seventh national league title in 2019-20 - their second in a row and sixth since 2007 - while adding a Cup triumph to complete the club's second-ever domestic double.
Converting such domestic supremacy into serious continental progress has so far proved beyond the club even under such celebrated - and expensively procured - managers as Dick Advocaat, Andre Villas-Boas, Luciano Spaletti, ex-Shakhtar Donetsk chief Mircea Lucescu and former Lazio player Roberto Mancini. Zenit reached the last 16 in 2011-12, 2013-14 and 2015-16 but have never progressed further.
Current coach Semak took on the mantle in 2018 and his expensively assembled squad has yet to convince on the grandest stage, as they have recorded only two victories in their last 12 Champions League games, losing eight.
Though they are equal on points with CSKA Moscow at the top of the league once more, after a weekend draw with Akhmat Grozny, the Lions face early elimination from the Champions League if they fail to upset the odds against the Eagles of Rome on Tuesday.
Lazio Champions League form: WDD
Lazio form (all competitions): WDWDDW
Zenit St Petersburg Champions League form: LLD
Zenit St Petersburg form (all competitions): LLWDWD
Lazio's Sergej Milinkovic-Savic, Senad Lulic, Thomas Strakosha and Gonzalo Escalante all missed out at the weekend due to continuing self-isolation and must wait testing to determine their availability on Tuesday.
Main man Ciro Immobile returned to great effect on Saturday and continues to rekindle his fruitful forward partnership with Joaquin Correa, while Luis Alberto should also keep his place after a short spell on the Lazio naughty step.
Former Aston Villa goalkeeper Pepe Reina will deputise if Strakosha is not ready to return, behind a familiar 3-5-2 formation.
Zenit keep faith in wayward striker Artem Dzyuba at the apex of their likely 4-1-3-2 setup, in which Colombian midfielder Wilmar Barrios is set to start in the holding role.
Ex-Barcelona winger Malcom recently returned from a knee injury and is a potent if unreliable option on the bench, while another key forward, Sardar Azmoun, is set to return after missing national duty with Iran through injury and could be utilised in Semak's Plan B.
Lazio possible starting lineup:
Reina; Hoedt, Acerbi, Radu; Lazzari, Parolo, Leiva, Alberto, Fares; Correa, Immobile
Zenit St Petersburg possible starting lineup:
Kerzhakov; Karavaev, Lovren, Rakitskiy, Santos; Barrios; Erokhin, Ozdoev, Zhirkov, Kuzyaev; Dzyuba
We say: Lazio 2-1 Zenit St Petersburg
Home side Lazio's recent upturn in fortunes has come amid a backdrop of controversy and COVID-19 complications - both issues which their Russian visitors have become accustomed to of late.
As Zenit have stalled recently, a repeat of their close-miss 'nearly win' in St Petersburg when these clubs last met is perhaps too much to ask.
Ciro Immobile and razor-sharp strike partner Joaquin Correa are poised to ignite the strongest Lazio Champions League challenge in years and will not easily be stopped here.