Roma rely on Henrikh Mkhitaryan, Pedro and Borja Mayoral in the Coppa Italia Round of 16 tie, while Spezia start Andrij Galabinov and Riccardo Saponara.
It kicks off at the Stadio Olimpico at 20.15 GMT and the winners go on to face Napoli in the quarter-final.
Antonio Mirante, Riccardo Calafiori and Nicolò Zaniolo are still out of action, while Edin Dzeko is rested with Chris Smalling.
Bryan Cristante therefore steps into the centre of the three-man defence, with Lorenzo Pellegrini moved into midfield, leaving Pedro and Mkhitaryan to support striker Borja Mayoral.
Bruno Peres gets the nod at right-wing-back rather than Rick Karsdorp, as Roma badly need a boost after their humiliating Derby della Capitale defeat to Lazio.
Curiously, these teams will also face off in Serie A at the Olimpico on Saturday at 14.00 GMT.
Spezia are still missing their top scorer M’Bala Nzola, along with Salva Ferrer, Jeroen Zoet and Federico Mattiello.
Once again, Titas Krapikas is chosen as their Coppa Italia goalkeeper, with January signing Riccardo Saponara getting his first start for the club.
Luca Vignali plays in defence, as he is suspended in Serie A following his red card just eight minutes into the 0-0 draw with Torino.
The big news is the return of Andrij Galabinov, as he had an extraordinary start to the season, scoring three goals in four Serie A appearances.
He then picked up a serious injury on October 4 and only made his comeback from the bench this weekend.
Here, he gets his first start in over three months.
Roma: Pau Lopez; Mancini, Cristante, Kumbulla; Peres, Pellegrini, Villar, Spinazzola; Pedro, Mkhitaryan; Borja Mayoral
Spezia: Krapikas; Vignali, Erlic, Ismajli, Ramos; Deiola, Leo Sena, Maggiore; Agudelo, Galabinov, Saponara