The Portuguese champions were eliminated in the group stages of last season's competition, whereas Leipzig return to Europe's top table after a year-long absence.
Two-time winners Benfica are one of European football's most famous clubs, but more recently they have had to content themselves with the role of conveyor belt of young talent to feed to more financially powerful outfits.
Joao Felix is the latest starlet to leave for big money, although in Ruben Dias and Florentino Luis they still boast two of football's most coveted youngsters - Manchester United have been heavily linked with both.
Good performances on the biggest stage will only add zeros to their valuations, as proved by one of their group-stage opponents last season Ajax.
The Portuguese giants will have been disappointed to crash out in the group last season, although they were paired alongside Ajax and Bayern Munich and this season's group looks a lot kinder, with Lyon and Zenit St Petersburg the other two teams in Group G.
Benfica's European journey came to an end at the hands of German opposition last season when they were beaten by Eintracht Frankfurt in the Europa League quarter-finals, while they were also beaten at home by Bayern on matchday one of the Champions League in 2018-19.
Bruno Lage's side have made a confident start to the defence of their record 37th domestic title with five wins from six games, keeping clean sheets in all of those victories while scoring 18 times.
A damaging 2-0 home defeat to bitter rivals Porto leaves them second to surprise package Famalicao in the standings, though, whereas their opponents on Sunday are sitting pretty at the top of the Bundesliga.
Julian Nagelsmann's side had a perfect record of four wins from four across all competitions heading into the international break and backed that up with a respectable 1-1 draw against champions Bayern Munich on Saturday.
Still relative new boys on the scene, Leipzig's third-place finish last term was enough to earn their second taste of the Champions League, having failed to progress beyond the group stages in 2017-18.
Leipzig have only ever won three of 12 European away games, though, including their only previous visit to Portugal during that Champions League champion.
Despite being included in pot four for the draw, Leipzig will fancy their chances of making it into the knockout stages for the first time, and anything they can get in these away games would be a big boost towards that landmark goal.
Benfica form: WWWLWW
RB Leipzig form: WWWWD
Benfica have a lengthy injury list for this time of the season, which Chiquinho added to when he limped out of the defeat to Porto.
The hosts do boast a man in form in Pizzi, though, with the attacker having scored again at the weekend to make it six goals in five games so far this term.
Former Tottenham Hotspur and Queens Park Rangers midfielder Adel Taarabt is also enjoying a new lease of life in Lisbon, earning his first international caps since 2014 during the recent break.
Leipzig have their own form player in Timo Werner, who has five goals in four league appearances so far and continues to be linked with a move to Bayern Munich.
Nagelsmann will be without Tyler Adams and Hannes Wolf, however, with the former sidelined since early August due to a metatarsal injury and the latter breaking his ankle on international duty with Austria Under-21s.
Benfica possible starting lineup:
Vlachodimos; Almeida, Dias, Ferreira, Grimaldo; Pizzi, Luis, Taarabt, Silva; De Tomas; Seferovic
Leipzig possible starting lineup:
Gulacsi; Mukiele, Konate, Orban; Klostermann, Laimer, Forsberg, Halstenberg; Sabitzer, Poulsen, Werner
We say: Benfica 1-1 Leipzig
Benfica are not easily beaten at home, but they are welcoming a Leipzig team in fine form and full of confidence. All of the matches in Group G are likely to be difficult to call, and we cannot separate these two on matchday one.
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