Roma captain Francesco Totti is out of Wednesday's Derby della Capitale against Lazio as he failed to recover from an ankle injury.
Totti has missed just two Rome derbies in his career, but the Giallorossi playmaker has been unable to train since sustaining the injury in last week's Champions League clash against Sporting Lisbon.
The absence of Totti, who is Roma's top scorer, will be a blessing for Lazio, who have had their share of injury woes this campaign.
Delio Rossi's men will be looking to bounce back from their poor start to the season which has seen them collect only 10 points from 9 games, and their home defeat to Udinese on Sunday left them just three points above the relegation zone.
The Biancoceleste will have to keep a close eye on Mirko Vucinic, who has been a sturdy replacement for Totti. Having scored the winner against Lisbon, Vucinic's goal handed Roma a 1-0 win at AC Milan at the weekend.
The outcome lifted Roma back to second in the standings, just three points behind leaders Inter.
Inter coach Roberto Mancini will be hoping from a favour from his former club Lazio at the Stadio Olimpico.
The Nerazzurri were held to a goalless draw at Palermo at the weekend and Mancini is aware of the threat Roma pose to his side's Scudetto ambitions.
"Roma is our main rival," said Mancini. "They were our main contenders even before the season started because they are the team that have the best quality in terms of play."
The unbeaten champions will have to overcome the absence of injured midfield duo Dejan Stankovic and Patrick Vieira when they host a Genoa side flying high. The Rossoblu have had a good start to the season following their return to the top flight and held Fiorentina to a draw at the weekend.
Struggling European champions Milan will be desperate to clinch a win to spark their season back to life when they travel to face Sampdoria. The Rossoneri will be relieved to play away from home considering they have not yet won a game at the San Siro this season.
Carlo Ancelotti's side, who lost at home to Roma, are struggling in Serie A and are already 11 points behind Inter in the race for the Scudetto. Samp are hardly in good health either going into this game following their 2-0 loss at Catania and star striker Antonio Cassano storming off the pitch of his own accord.
Juventus look to get back on the winning track after slipping to a controversial 3-1 defeat at Napoli on Saturday night, a result that saw them drop to fourth in the standings. The Bianconeri are at home to Empoli on Wednesday and will be hoping to reduce the gap between themselves and Inter before the two go head-to-head on Sunday night.
Third-placed Fiorentina, still unbeaten in all competitions this season, face a stern test of their credentials when they host Napoli in Florence. The Azzurri are three points behind the Florence-based side in sixth place after a confident start this season.
Palermo will be in a positive frame of mind going into their clash against Parma in Sicily after holding Inter to a goalless draw, but the Rosanero will be looking for their first win in four games.
Udinese will be hoping to build on their 1-0 win at Lazio when they host Torino at the Stadio Friuli. The Zebrette have made a team in top form, and will be looking to keep hold of fifth place.
Atalanta will be keen to hold on to their place in the top half of the Serie A when they host Cagliari. Gigi Del Neri has guided the Bergamo side to seventh following their win at Empoli.
In other games, winless duo Reggina and Livorno go face-to-face in the battle of the bottom two in Reggio de Calabria and Catania visit Siena in another relegation dogfight.