Jose Mourinho's men will not only be aiming to book a quarter-final clash with arch-rivals Lazio but are also seeking a slice of revenge for last year's cup defeat to the Grigiorossi.
Match preview
While Roma have endured a mixed first half of the Serie A season, sitting seventh in the standings at the end of 2023, their progress in the Europa League suggests that deep runs in cup competition could again be on the cards.
Europa Conference League winners in 2022 and beaten finalists in UEFA's second-tier tournament last term, the Giallorossi have become renowned for navigating knockout rounds since Jose Mourinho took charge.
Last year's Coppa Italia quarter-final tie with Cremonese, however, did not go to plan, and Roma were unexpectedly eliminated at Stadio Olimpico, losing 2-1 in front of their own fans.
Having been given a bye through the earlier rounds this time, due to their top-eight finish in last season's league table, the capital-city club now return to the Coppa with a game against the very same opponents.
Given Mourinho's undying thirst for silverware, their ultimate aim will be to move clear of current holders Inter Milan and sit alone behind Juventus, who are the only club to have won the Coppa Italia more times than Roma's tally of nine.
A 1-0 league defeat to Juve on Saturday night - which continued their string of failures against the top sides - leaves Roma with plenty of work left to secure a top-four spot in Serie A, but they are tough to beat on home soil and will have vengeance on their minds in midweek.
Almost a year after unexpectedly triumphing in their first-ever Coppa clash with Roma, Cremonese return to the Eternal City with hope of repeating their feat.
The Grigiorossi certainly have fond memories of last season's competition, in which they defied the odds to reach the semi-finals before losing 2-0 to Fiorentina, with victories over both Roma and Napoli sure to live long in the memory.
This term, Giovanni Stroppa's side progressed to the last 16 by beating Cittadella - who they currently sit one point behind in the Serie B standings - for the second time in four days at the end of October, although it took a late extra-time winner from Massimo Coda to see them through against 10-man opponents.
They had previously defeated Stroppa's former club Crotone in the first round, played at the very start of the season; again, the teams were tied after 90 minutes but Cremonese prevailed in the end, winning 3-1 at Stadio Zini.
Since then, the side relegated from Italy's top flight last season have kept themselves in contention for an immediate return, even if a dramatic Boxing Day defeat to promotion rivals Palermo saw them slip nine points behind Serie B leaders Parma. Reaching the promised land again is Stroppa's priority, but on Wednesday, his team will have another taste of the big time.
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Cremonese Coppa Italia form:
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Team News
Roma are bound to rotate their squad amid an intense schedule - Serie A is not having a winter break this year - but Jose Mourinho will be without two options for Wednesday's Coppa Italia tie: Houssem Aouar has departed for international duty with Algeria, while Evan Ndicka is set to represent host nation Ivory Coast at the AFCON.
Marash Kumbulla is reportedly ready to return, though, following eight months on the sidelines with an ACL injury. The Albanian defender should start on the bench; English duo Chris Smalling and Tammy Abraham remain out of action.
Mourinho could rest Romelu Lukaku and Paulo Dybala, offering Andrea Belotti a chance to impress, and fringe players including Sardar Azmoun, Renato Sanches and Zeki Celik may also be involved from the first whistle. The latter will be particularly motivated after scoring an own goal in last year's quarter-final contest.
Meanwhile, Cremonese's most notable absentee is Cristian Buonaiuto, who recently underwent surgery on a serious thigh injury and will be unavailable for at least three months.
Alessio Brambilla is back in full training but is not likely to be selected, and Yuri Rocchetti remains sidelined; meanwhile, ex-Roma midfielder Andrea Bertolacci has just re-joined Turkish side Fatih Karagumruk.
Like Mourinho, Cremo coach Giovanni Stroppa prefers a 3-5-2 formation, with Massimo Coda and Franco Vazquez generally paired together up front; however, David Okereke, Felix Afena-Gyan - who started his stay in Italy with Roma - and veteran striker Daniel Ciofani are all in contention too.
Roma possible starting lineup:
Svilar; Celik, Cristante, Llorente; Karsdorp, Bove, Sanches, Pellegrini, El Shaarawy; Azmoun, Belotti
Cremonese possible starting lineup:
Jungdal; Antov, Ravanelli, Bianchetti; Ghiglione, Collocolo, Castagnetti, Pickel, Sernicola; Vazquez, Okereke