A hamstring injury has ruled Kevin de Bruyne out of action for between four and six weeks.
The Belgian was withdrawn just shy of the hour mark in Manchester City's 2-0 win at home to Aston Villa in midweek.
It's a huge blow to City's title hopes, with the club currently two-points off leaders Manchester United with a game in hand.
"Kevin, the doctor had to review the scan this morning, and he will be out between four and six weeks," his manager Pep Guardiola confirmed.
It means De Bruyne will definitely miss Premier League games with Liverpool, Tottenham, and perhaps Arsenal too.
The 29-year old trails only Harry Kane in terms of Premier League assists this season, with 10. He's also contributed 3 goals to City's tally.
Should De Bruyne's injury take the full six weeks to heal, he will miss the first leg of City's Champions League last-16 tie with Borussia Monchengladbach.
And if that happens, the Manchester derby at the Etihad on March 6 would also become a concern.
"We have to move forward," said Guardiola. "I'm not saying that nobody doesn't know about his importance.
"Unfortunately for him and us, he'll be out for an important part of the season, and we have to find a solution because everyone's struggling in this situation, and we have to adapt.
"The players don't want to get injured, but they are human. Why in the FA Cup can we use five subs but in the league not? It is a different competition. Is it a special one? It's not just because it's Kevin. It is everyone for the past five seasons. It is too many games."
Guardiola will also be without Kyle Walker for this weekend's FA Cup 4th round tie with Cheltenham.
"Kyle had a big impact kick in his hips, but just a kick, so is not available tomorrow but we wish he is available for the next game," said the City boss.