Lazio start Joaquin Correa behind Ciro Immobile, while Danilo Cataldi clashes with Kevin Strootman again in a crunch tie with Olympique Marseille.
It kicks off at the Stadio Olimpico at 17.55 GMT.
The Aquile put themselves in a very strong position with a 3-1 victory at the Stade Velodrome and will be qualified for the Round of 32 this evening if they win and Apollon Limassol don’t beat runaway group leaders Eintracht Frankfurt.
Marseille were in the Europa League Final last season, but amassed only one point from the opening three games in this group and a defeat here will automatically eliminate them from the competition.
Coach Rudi Garcia returns to the Olimpico after his spell at Roma, but is under pressure following three consecutive defeats between Europe and Ligue 1.
Their fans have been barred from buying tickets for this game after repeated incidents of crowd trouble, both inside and outside the stadium.
Star names like Dimitri Payet and Kostas Mitroglu are benched, but Florian Thauvin starts along with ex-Milan players Lucas Ocampos and Adil Rami.
UEFA have this as a 5-4-1 formation, but it's more realistically a 3-4-3.
Lazio welcome back Correa from suspension and he is thrown in as support for Immobile.
Caicedo had been due to start, but pulled out at the last minute with a muscular problem.
Lucas Leiva, Milan Badelj and Senad Lulic are out of action, Sergej Milinkovic-Savic and Stefan Radu are rested.
The midfield tussle between Cataldi and Strootman should be fascinating and fiery, because they famously clashed during a Rome Derby in December 2016.
Strootman had just scored and during his celebrations squirted water from a bottle into the face of Cataldi, who was on the Lazio bench.
When Cataldi got up to grab the back of Strootman’s jersey and give a light tug, the Dutchman went down dramatically, sparking a touchline brawl.
While Cataldi was sent off, Strootman was later given a two-match ban for simulation.
Lazio are only two goals away from becoming the fourth club to score 100 in the Europa League, group stage to Final, after Villarreal, FC Salzburg and Athletic Bilbao.
Lazio: Strakosha; Luiz Felipe, Acerbi, Wallace; Marusic, Parolo, Cataldi, Berisha, Durmisi; Correa; Immobile
Lazio bench: Proto, Rossi, Luis Alberto, Bastos, Milinkovic-Savic, Caceres, Murgia
Marseille: Pele; Rami, Luiz Gustavo, Caleta-Car; Sakai, Lopez, Strootman, Sanson, Ocampos; Thauvin, Njie, Lopez
Marseille bench: Mandanda, Rolando, Radonjic, Payet, Mitroglou, Sarr, Hubocan
Ref: Bezborodov (RUS)
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