Manchester City and England defender John Stones will be out for between four and five weeks after suffering a muscle injury in training.
Stones suffered the injury in Ukraine on Tuesday, where City are preparing for Wednesday's Champions League group game with Shakhtar Donetsk.
The injury is a setback for City, who are also without Aymeric Laporte until January or February because of injury.
It leaves City with one established central defender in Nicolas Otamendi.
The injury comes as City prepare for a busy period of games in the Premier League, Champions League and Carabao Cup.
Stones, 25, could miss up to eight league and cup matches for reigning Premier League champions City, who suffered a surprise 3-2 defeat at newly-promoted Norwich last Saturday.
"For me as a manager it is an incredible challenge," said City boss Pep Guardiola after revealing the news about Stones' injury during a news conference.
"But I believe in something people don't know about - spirit and commitment. We will make steps forward to solve this problem."
After facing Shakhtar, City entertain Watford on Saturday before playing Championship Preston at Deepdale in the third round of the EFL Cup next Tuesday.
City are away to Everton on 28 September, host Dinamo Zagreb in the Champions League on 1 October before welcoming Wolves to Etihad Stadium five days later.
After the international break, Pep Guardiola's side are at Crystal Palace on 19 October and then host Italian side Atalanta in the Champions League three days later.
France centre-back Laporte, 25, had surgery on his right knee after being carried off during the 4-0 win over Brighton on 31 August.
City are second in the Premier League table, five points behind leaders Liverpool.