Both teams have much to prove, as despite reaching several semi-finals since the start of last year, United have yet to progress any further during that time - meanwhile, the under-performing Serie A side arrive in England amid some dismal domestic form.
Here, Sports Mole rounds up all of the latest team news for the two clubs ahead of Thursday's game.
MANCHESTER UNITED vs. ROMA
MANCHESTER UNITED
Out: Anthony Martial (knee), Phil Jones (knee)
Doubtful: None
Sports Mole's predicted XI: De Gea; Wan-Bissaka, Lindelof, Maguire, Shaw; Fred, McTominay; Pogba, Fernandes, Rashford; Cavani
ROMA
Out: Nicolo Zaniolo (ACL), Pedro (thigh), Gianluca Mancini (suspended)
Doubtful: Riccardo Calafiori (thigh), Marash Kumbulla (meniscus)
Sports Mole's predicted XI: Lopez; Cristante, Smalling, Ibanez; Karsdorp, Diawara, Veretout, Spinazzola; Pellegrini, Mkhitaryan; Dzeko