While the Giallorossi lost out to Sevilla in last term's showpiece, Moldovan champions Sheriff have never before progressed to the last 16.
Following their penalty-shootout defeat in June's bitterly contested Europa League final, speculation persisted that Roma would lose their controversial head coach Jose Mourinho during the off-season.
However, the veteran tactician's love affair with the Eternal City continues into the final year of his contract, and he will now get another shot at adding the trophy to Roma's Europa Conference League crown of 2022.
After a slow start to the new Serie A season, in which the Giallorossi picked up just one point from their first three games, new signing Romelu Lukaku scored on his first start for the club in Sunday's 7-0 thumping of Empoli, with strike partner Paulo Dybala coming close to completing a hat-trick.
Although Dybala's second-half free-kick struck the bar, Roma roared past their timid Tuscan opponents at Stadio Olimpico, and Lukaku now returns to a competition in which has found the net in each of his last 11 appearances - that represents the longest such streak of any player in Europa League or UEFA Cup history.
As Mourinho is a past master at navigating continental competition, and Roma have progressed from their group in all five previous Europa League appearances, he will surely expect to reach the last 16 without too much fuss this time around.
The 2022-23 runners-up in both Swiss and Czech leagues also await later on in the schedule, but first Roma must travel to Transnistria, home of the reigning Moldovan champions.
After exiting the Champions League preliminaries to Maccabi Haifa, Sheriff Tiraspol came through Europa League qualifying to make their sixth group stage appearance, seeing off BATE Borisov and KI Klaksvik to join Roma, Servette and Slavia Prague in Group G.
Each time they have previously participated in Europe's second-tier club tournament, Sheriff have failed to reach the last 16, but in last season's Conference League they made that stage before being knocked out by Nice.
They now prepare for their first meeting with Roma, having met only one other Serie A side before: two encounters with Inter Milan in the 2021 Champions League group phase ended in defeat, but the Moldovan side did spring a major shock that year by beating Real Madrid.
After a spell in charge of Moldova's national team, Roberto Bordin has since returned to the club; the 58-year-old represented teams such as Napoli and Atalanta during his playing days, but his managerial career has mostly taken place in eastern Europe.
Bordin's Sheriff side have lost only one of their last nine matches in all competitions following a 5-1 defeat of Florești last weekend, and they sit second in the Moldovan Super Liga.
Attempting to secure their ninth domestic title in a row this season, the Zholto-Chornyye are also hoping to break new ground in Europe - but they have been set a particularly tough assignment to start with.
While long-term absentees Tammy Abraham and Marash Kumbulla will certainly not be available for Roma, doubts remain about the fitness of Chris Smalling and captain Lorenzo Pellegrini ahead of their Europa League opener.
Having rotated goalkeepers in cup competitions last season, Jose Mourinho may switch Rui Patricio for Mile Svilar on Thursday evening, while Smalling's availability would allow changes to the back three - Gianluca Mancini or Diego Llorente could therefore be rested.
Despite Abraham's absence, Mourinho now has plenty of viable options up front. With Sardar Azmoun not registered for UEFA competition, though, either Paulo Dybala, Andrea Belotti or Stephan El Shaarawy could partner Romelu Lukaku, who has racked up 15 goals in his last 11 Europa League games, covering spells at Everton and Inter.
Meanwhile, the hosts will turn to Henrique Luvannor for inspiration in the final third: the Brazil-born Moldova international has scored in both of his last two outings, including a crucial penalty in last month's playoff win over KI.
Moroccan midfielder Amine Talal found the net three times during qualifying and should start at Sheriff Arena, where Roberto Bordin may opt for a more conservative 4-1-4-1 formation to combat Roma's substantial firepower.
Sheriff Tiraspol possible starting lineup:
Koval; Zohouri, Garananga, Tovar, Artunduaga; Ademo; Ngom Mbekeli, Talal, Vardar, Ricardinho; Luvannor
Roma possible starting lineup:
Svilar; Mancini, Llorente, Ndicka; Karsdorp, Bove, Cristante, Aouar, Zalewski; Belotti, Lukaku
We say: Sheriff Tiraspol 1-2 Roma
With confidence high after posting the club's biggest Serie A victory since 2006, Roma should be able to navigate a tricky away fixture to start their Group G campaign. Although Jose Mourinho may make several changes, the Giallorossi's squad depth is greater these days and Sheriff will come up short on home soil.
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