Sergio Aguero completed a hat-trick and a dramatic late turnaround as City beat Bayern Munich 3-2 to claim a maiden Group E win on matchday five and keep their campaign alive.
A win or a score draw will see Manuel Pellegrini's team into the last 16, providing CSKA Moscow do not match either result in Munich.
But Aguero, the Premier League's top scorer this season, twisted his knee during the opening stages of Saturday's battling 1-0 win over Everton.
City are still waiting to learn the extent of the injury suffered by their talisman, but he will miss out in the Italian capital for a game that is also expected to come too soon for David Silva (knee) and captain Vincent Kompany (hamstring).
Yaya Toure serves the second game of a three-match suspension to stretch City’s resources in midfield, though Fernandinho is poised to return.
Teenage forward Jose Angel Pozo replaced Aguero against Everton and could feature once more, with Stevan Jovetic nursing a hamstring complaint, although Edin Dzeko may start earlier than planned having recently returned from a calf injury.
Samir Nasri, whose importance to City's attacking play is increased in Silva's absence, remains confident the English champions can avoid a third group-stage elimination from the Champions League in four seasons.
"If we play our game, we will win against Roma," he told beIN Sport. "The greatest risk is to play with pressure and to have this apprehension.
"If we don't ask questions, and we play our game, then we will do it. We have more qualities.
"If we are eliminated from the Champions League, this is not the fault of the coach, it is the players who are on the pitch."
Bayern’s 7-1 demolition of Roma at the Stadio Olimpico is very much an exception this term, with Rudi Garcia's team having won seven from seven at home in Serie A until Sassuolo left with a 2-2 draw on Saturday.
Despite being 2-0 down and reduced to 10 men following Daniele De Rossi’s red card, Roma claimed a share of the spoils thanks to Adem Ljajic's brace.
Similar resilience will serve them well on Wednesday night, when former Arsenal forward Gervinho believes the pressure will be firmly on City's expensively assembled squad.
He told The Sun on Sunday: "City are obliged to win. They have all the pressure. Not Roma. City are in the same period that Chelsea used to be before they won [the Champions League]. It becomes complex until you win the trophy.
"The trophy their investors expect to win is the Champions League. City have a lot more pressure than us given the expense they have undertaken to create this team."
Provided CSKA do not win at the Allianz Arena, a goalless draw would be enough to see Roma through on their head-to-head record over City.
Roma right-back Maicon is set for a reunion with the club he represented during the 2012-13 season, with Vasilis Torosidis (calf) set to miss out once more.
