The Russian giants enter Europe at this stage courtesy of their second-placed league finish last term, while Benfica took third place in the 2020-21 Primeira Liga season.
Perhaps best known for his trophy-laden stint in the Benfica dugout, Vitoria has since swapped sunny Portugal for Spartak Moscow, who have endured mixed fortunes during the early weeks of the 2021-22 Russian Premier League season.
A 1-0 defeat to Rubin Kazan on the opening weekend preceded victory by the same scoreline over Krylya Sovetov on July 30, as Aleksandr Sobolev struck the game's only goal from the penalty spot on the 68-minute mark to kickstart Spartak's domestic season at the second time of asking.
Securing a first league title since the 2016-17 season is undoubtedly on the agenda for Vitoria, but the former Champions League group-stage regulars have not plied their trade at that stage of the tournament since the 2017-18 campaign, during which they drew with Liverpool and thrashed Sevilla 5-1 before being forced to settle for third.
Since gleaning those stellar results, it has been a painful couple of years without continental competition for the Red and Whites, whose most recent European campaign saw them drop out to PAOK during this stage of 2018-19 Champions League qualifying before a group-stage Europa League exit.
A two-time league winner during his time at the Benfica helm, Vitoria's three-and-a-half year stay with the Portuguese side remains the most successful of his managerial career so far, but the 51-year-old cannot let even a hint of sentimentality creep in this week.
Meanwhile, Wednesday's first leg in Moscow represents the first competitive fixture of Benfica's 2021-22 season, with Jorge Jesus's side not due to kick off their Primeira Liga season until August 7 against Moreirense.
The Portuguese powerhouses may therefore be behind in their preparations compared to Spartak, but Jesus has overseen an unbeaten pre-season period at the helm, claiming victories over Casa Pia, Almeria and Lille before playing out a 1-1 draw with Marseille in their final exhibition match.
With their recent reign of dominance on the Portuguese football scene ended by Porto and extended by Sporting Lisbon, Jesus has his sights firmly set on regaining the Primeira Liga crown, as evidenced by his transfer activity during a busy summer of incomings and outgoings.
Benfica have garnered respectable fees from the sales of Pedrinho, Nuno Tavares and Franco Cervi over the summer period, but a trio of high-profile incomings of Joao Mario, Soualiho Meite and Ukrainian frontman Roman Yaremchuk represent an early statement of intent from Jesus ahead of this first-leg battle.
Coincidentally, Benfica also suffered a shock exit to PAOK at this stage of Champions League qualifying last season, and the Portuguese side overcame Spartak Moscow 2-0 on home soil after a 2-1 defeat away from home in the 2012-13 Champions League group stages.
Spartak defender Pavel Maslov continues to recuperate from hip inflammation and will not take to the field in the first leg, while Aleksandr Selikhov is nursing a fractured finger and will also miss out.
Former Chelsea winger Victor Moses is in line to feature out wide for the hosts this week, but muscular issues prevented Quincy Promes from taking part at the weekend and he remains a doubt for midweek.
West Ham United-linked Alex Kral will hope to force his way back into the midfield after a substitute cameo at the weekend, while Ezequiel Ponce has just completed an unsuccessful Olympics campaign with Argentina and is back in the squad.
Yaremchuk's arrival at Benfica comes at an ideal time as Darwin Nunez continues to recover from knee surgery, but Wednesday's game will be too soon for the Ukrainian to be involved.
Brazilian midfielder Gabriel has also been left out of the squad as he trains away from the first team, meaning that Adel Taarabt and Julian Weigl could form the midfield duo as former Tottenham Hotspur loanee Carlos Vinicius pushes for a start up front.
Spartak Moscow possible starting lineup:
Maksimenko; Rasskazov, Gigot, Dzhikiya, Lucas; Kral, Zobnin; Moses, Bakaev, Promes; Sobolev
Benfica possible starting lineup:
Vlachodimos; Verissimo, Otamendi, Vertonghen; Gilberto, Taarabt, Weigl, Grimaldo; Pizzi, Seferovic, Silva
We say: Spartak Moscow 0-1 Benfica
Spartak Moscow may have a slightly greater competitive edge heading into the first leg having already kicked off their league proceedings, but Benfica's pre-season form is something to be admired.
A cagey encounter should be on the menu as both teams seek to avoid any fatal errors before next week's second leg, and we can envisage Benfica nicking a goal to take a slender advantage back to Portugal.
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