David Silva and Mario Balotelli will miss Manchester City's crunch Premier League clash with Arsenal on Wednesday night.
The duo have both sustained knee injuries which will rule them out of the Emirates Stadium encounter, with Spain winger Silva possibly facing two weeks on the sidelines.
Italy striker Balotelli, who bagged a hat-trick in his last outing against Aston Villa, missed the New Year's Day victory over Blackpool and is still not fit enough to return.
Eastlands boss Roberto Mancini admits it is a significant setback to his side as they look to keep pace at the top of the table.
"It is a big problem," said Mancini. "Neither of them will be available."
Silva in particular will be a major loss at the Emirates given his growing influence on the Blues in recent weeks.
"David has been an important player for us and has been doing well recently," said Mancini.
"Hopefully, he will be back for the Wolves game on January 15. Mario might be back for the FA Cup tie at Leicester on Sunday."
Mancini claims that his side are still outsiders in what he accepts is now a five-team pursuit of the title.
City go into the latest round of fixtures joint top with neighbours Manchester United, although they have played two games more than the men from Old Trafford.
And Mancini, who has previously claimed that Chelsea were firm favourites for the championship, feels that City's inexperience in such situations could count against them.
"Arsenal, Chelsea, United and Tottenham all have more experience than us," he said. "Probably one of those four teams will win the title.
"We just want to work, so we can improve and try to keep getting better."