Roma are forced into massive changes, losing Pau Lopez and Edin Dzeko, so Nicolò Zaniolo faces his old club as a False 9, while Inter revamp their midfield.
It kicks off at San Siro at 19.45 GMT, you can follow all the build-up and action as it happens on the LIVEBLOG.
This is a huge clash between the new Serie A leaders, who leapfrogged Juventus last week, and fourth-placed Roma.
Both sides have won five out of their last six league games and are on sparkling form, with important European fixtures coming up midweek.
However, they are also forced to reshuffle their squads due to an injury crisis that is only getting worse.
Dzeko has not fully recovered from a bout of flu and is only on the bench, while goalkeeper Pau Lopez picked up a muscular injury in training this morning.
With Justin Kluivert, Javier Pastore, Federico Fazio, Davide Zappacosta and Bryan Cristante all out of action, the only available striker is Nikola Kalinic.
Instead, Paulo Fonseca has chosen to experiment with Italy international Zaniolo in a False 9 role, supported by Henrikh Mkhitaryan (returning to the starting XI after a long lay-off), Lorenzo Pellegrini and Diego Perotti.
Zaniolo is particularly eager to make his mark at San Siro, as he was in the Inter youth academy, but sold to Roma as part of the deal for Radja Nainggolan.
The 20-year-old is one of their top scorers for this season, netting five goals in 18 competitive games, along with one assist. He was suspended for last week’s 3-1 victory away to Verona.
Veteran goalkeeper Antonio Mirante fills in for Pau Lopez, while Davide Santon is chosen rather than Leonardo Spinazzola.
Inter have to readjust too, as while Romelu Lukaku is fit enough to start with Lautaro Martinez despite also suffering from flu, the midfield is completely revamped.
Roberto Gagliardini has joined Stefano Sensi, Nicolò Barella and Alexis Sanchez on the treatment table, so Borja Valero steps in, with Antonio Candreva and Cristiano Biraghi on the wings.
Diego Godin gets the nod rather than Danilo D’Ambrosio in defence.
The last three Serie A meetings between these teams all ended in a draw, so we could see four in a row for the first time since 1967.
Inter have won only three of their last 14 Serie A home games with Roma, drawing six and losing five. Their most recent victory in this fixture was in 2015.
Inter: Handanovic; Godin, De Vrij, Skriniar; Candreva, Vecino, Borja Valero, Brozovic, Biraghi; R Lukaku, Lautaro Martinez
Inter bench: Padelli, Berni, Ranocchia, Politano, Asamoah, Lazaro, Dimarco, Esposito, Agoume, D’Ambrosio, Bastoni
Roma: Mirante; Santon, Mancini, Smalling, Kolarov; Veretout, Diawara; Mkhitaryan, Pellegrini, Perotti; Zaniolo
Roma bench: Cardinali, Fuzato, Juan Jesus, Dzeko, Cetin, Under, Kalinic, Florenzi, Spinazzola, Antonucci
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