Roma have little room for squad rotation and rely on Edin Dzeko with Cengiz Under and Stephan El Shaarawy against a SPAL side trying to stop the rot.
It kicks off at 14.00 UK time (13.00 GMT).
The Giallorossi went into the break for international duty on a run of four consecutive victories in all competition, so a fifth would be their best streak since November 2017.
On the other hand, SPAL have lost four on the bounce and are one away from matching their all-time negative record set in 1964.
With an eye to the Champions League and another on the many players who were representing their countries, Eusebio Di Francesco would probably have liked more room for manoeuvre when it comes to squad rotation.
However, Patrik Schick, Diego Perotti, Aleksandar Kolarov, Daniele De Rossi and Rick Karsdorp are unavailable, though Javier Pastore is back in the squad.
Lorenzo Pellegrini therefore takes the trequartista role he is already making his own, flanked by Stephan El Shaarawy and Cengiz Under, with Edin Dzeko having to do extra work in attack.
Justin Kluivert had been tipped for a start, but he is on the bench again.
There’s another chance for Luca Pellegrini to shine at left-back in his second Serie A start, while Bryan Cristante partners Steven Nzonzi.
Kostas Manolas is rested in favour of Ivan Marcano in the back four.
SPAL have captain Dias Felipe suspended, with Jasmin Kurtic, Johan Djourou and ex-Roma youth product Federico Viviani injured.
Leonardo Semplici shakes things up and starts two centre-forwards, Andrea Petagna and Alberto Paloschi, with Kevin Bonifazi returning from a long injury lay-off to fill the gaps in defence.
Manuel Lazzari is the one to watch, as he caused Inter huge problems in an unlucky defeat to the Nerazzurri.
A particular surprise sees Vanja Milinkovic-Savic - younger brother of Lazio midfielder Sergej - start in goal.
SPAL have only beaten Roma once in the Capital in Serie A, 2-0 back in September 1965, around six draws and nine defeats.
Roma: Olsen; Florenzi, Fazio, Marcano, Luca Pellegrini; Nzonzi, Cristante; Under, Lorenzo Pellegrini, El Shaarawy; Dzeko
SPAL: Milinkovic-Savic; Cionek, Vicari, Bonifazi; Lazzari, Missiroli, Valdifiori, Valoti, Costa; Paloschi, Petagna
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