Villarreal striker Giuseppe Rossi is set to be sidelined until April after it was confirmed that he suffered cruciate ligament damage in the 3-0 defeat to Real Madrid.
The Italy international was replaced after 60 minutes of the match at the Santiago Bernabeu on Wednesday and scans have revealed the extent of the knee injury.
He will now miss most of the rest of the season, including the rest of the UEFA Champions League group campaign.
Villarreal's 2-1 defeat at Manchester City last week left them without a point at the bottom of Group A and they welcome Roberto Mancini's men to El Madrigal for the reverse fixture next Wednesday.
A statement on Villarreal's official website read: "Worst fears have been confirmed. Villarreal's Italy striker Giuseppe Rossi seriously injured in his right knee in the match against Real Madrid at the Santiago Bernabeu and is out for six months."
The club said the 24-year-old was set to undergo surgery on his anterior cruciate ligament on Thursday night.
The news of the severity of the injury is a major blow to the Yellow Submarine, who have endured a dreadful start to the new Primera Division campaign.
Juan Carlos Garrido's side, who have become Champions League regulars, lie in the relegation zone with only seven points from their opening nine matches.
Rossi is perhaps the player they can least afford to be without.
The former Manchester United forward scored 32 goals in all competitions last season and his form saw him linked with a move to Barcelona in the summer.
Villarreal are now seriously short of options in attack as their other senior striker Nilmar is also out with a knee injury for at least another month.