For the second season running these clubs are meeting in the semi-finals, but events in the first leg make the new German champions favourites to overturn last year's result.
Match preview
In addition to gaining revenge for losing to Roma at this stage 12 months ago, Leverkusen took a giant stride towards meeting either Marseille or Atalanta BC in the Europa League final by running out 2-0 winners at Stadio Olimpico.
Having withstood a scare when Romelu Lukaku struck the crossbar, Die Werkself produced several chances themselves, so goals from star man Florian Wirtz and midfield engine Robert Andrich were just reward for their impressive performance in an intimidating arena.
Following a ninth win from 11 Europa League fixtures this season, the Bundesliga winners are now only 90 minutes away from booking their place in Dublin later this month, and an historic treble remains very much on the cards for a team that simply refuses to be beaten.
Sensationally crowned German champions with several weeks to spare, Leverkusen have recently produced several late goals to keep their proud undefeated streak intact, but they easily extended that run to 48 games with a 5-1 victory over Eintracht Frankfurt on Sunday.
Benfica's longstanding European record - set between December 1963 and February 1965 - has now been matched, so keeping Roma at bay would cement their place in history.
A trip to Berlin for the DFB-Pokal final - where Leverkusen will meet second-tier strugglers Kaiserslautern - is also on the agenda, and becoming the first team to go through an entire Bundesliga campaign without losing would place the cherry on top.
Much-coveted coach Xabi Alonso has already confirmed he will stay in situ for another year at least, so everything is in place for the 1988 UEFA Cup winners and 2002 Champions League runners-up to make their first Europa League final appearance.
Despite losing at home for just the second time in 33 UEFA competition matches, Roma have not abandoned their quest to make a third straight European final - but the outlook looks bleak for the Eternal City side.
Then under Jose Mourinho, the Giallorossi's 1-0 aggregate win over Leverkusen in last year's Europa League semi-finals preceded defeat to Sevilla in the decider, and they had lifted the inaugural Europa Conference League trophy just 12 months previously.
Current coach Daniele De Rossi, who is aiming to follow his predecessor's path in Europe and oversaw a quarter-final win over AC Milan, has suffered only four losses in 22 matches since taking charge, following Mourinho's mid-season exit.
After a fluent start to his Roman reign, De Rossi's side have averaged a more modest one goal per game over their past 11 outings; slipping to sixth place in the Serie A standings, tied on points with fifth-placed Atalanta, who have one game in hand.
Like Xabi Alonso, De Rossi recently agreed to continue his work into next season, but being held to a 1-1 home draw by Juventus at the weekend - despite taking the lead through Lukaku - means that a prized top-five finish is in some doubt.
Roma could yet qualify for the Champions League via a Europa League win instead, but an improbable comeback is required if they are to become just the third team to reach successive finals in Europe's second-tier tournament.
Bayer Leverkusen Europa League form:
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Bayer Leverkusen form (all competitions):
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Roma Europa League form:
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Roma form (all competitions):
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Team News
Xabi Alonso rotated his squad substantially against Frankfurt, making a total of eight changes to the team that started in Italy, but a much more familiar lineup will attempt to guide Leverkusen to second-leg success.
Unburdened by injuries or suspensions, the Spanish coach is set to recall Jonathan Tah, Jeremie Frimpong, Alex Grimaldo and several others to the hosts' first XI.
Florian Wirtz enjoyed a rare rest at the weekend, but the Germany forward will also return: following his strike in the first leg, the 20-year-old has now netted 12 Europa League goals at this early stage of his career.
He has, however, still got a long way to catch competition specialist Romelu Lukaku, who has scored seven goals in this season's edition and 27 times overall.
Roma's main marksman should be supported by Paulo Dybala and Stephan El Shaarawy in the visitors' final third, providing Dybala can overcome a minor muscular problem that saw him withdrawn halfway through Sunday's game against former club Juventus.
Right-back Zeki Celik is available after serving a suspension last week, so Rasmus Kristensen - who is not on Roma's UEFA squad list - will make way, while Leonardo Spinazzola and Chris Smalling may both be brought back in to add experience and European know-how.
Bayer Leverkusen possible starting lineup:
Kovar; Tapsoba, Tah, Hincapie; Frimpong, Andrich, Xhaka, Grimaldo; Wirtz, Adli; Schick
Roma possible starting lineup:
Svilar; Celik, Mancini, Smalling, Spinazzola; Cristante, Paredes, Pellegrini; Dybala, Lukaku, El Shaarawy
We say: Bayer Leverkusen 1-0 Roma (Bayer Leverkusen win 3-0 on aggregate)
Roma's away record is far from special, and Leverkusen are an immovable object, so an almighty upset is required to send the away side through.