Sergio Aguero has been ruled out of Manchester City's clash against Crystal Palace this weekend while Claudio Bravo will not play again this season.
Manager Pep Guardiola has also revealed playmaker David Silva remains a doubt despite returning to training and defender John Stones is still sidelined.
Aguero, City's top scorer with 31 goals this term, suffered a groin injury in the latter stages of last week's draw at Middlesbrough and has been unable to prove his fitness for Saturday's Premier League visit of Palace.
Goalkeeper Bravo missed the trip to Boro after being substituted with a calf injury in the previous game against Manchester United and it now seems his troubled first campaign at the Etihad Stadium is over. Stones and Silva have also been absent in recent weeks.
Guardiola, asked first about Aguero's fitness at his latest press conference, said: "No. Hopefully the next one but for this game, no. He is not fit."
On Silva he added: "Yesterday was the first training session. I don't know if he will be ready for tomorrow. No, after the reaction in the semi-final of the FA Cup, he's still not perfect."
Asked further about injuries, he said: "Bravo isn't coming back until next season, Stones maybe in the last games."
The encounter with Sam Allardyce's Palace is the first of three successive home games City hope will see them cement a place in the top four before their final-day trip to Watford.
City, currently fourth, remain locked in a tight battle for Champions League qualification with Liverpool, Manchester United and Arsenal.
Guardiola said: "It's still in our hands if we are able to win the four games, but that's so complicated.
"I know how tough Crystal Palace are. They beat Arsenal, Chelsea and Liverpool.
"We have Leicester, the last champions, then we have West Brom and Tony Pulis, who are always complicated.
"But it is in our hands. We will see if we are able to make our step forward to qualify. If we win all four games we will definitely be in the Champions League and maybe in the third position. It depends on us."
Aguero's absence means Gabriel Jesus, who recently returned from injury himself, could lead the line alone.
Guardiola said of the Brazilian: "He was important the last two weeks but I would prefer to play with Sergio together. With our lack of goals, it would have been better."
Palace are now close to confirming their top-flight status for another season having been rejuvenated since Sam Allardyce took charge in December.
The Eagles have lost their last two games but remain six points above the bottom three.
Guardiola said: "Sam Allardyce is a top, top coach. He is able to get teams who are in a bad situation, and they are simple and clear about what they do. What they do, they do perfect.
"When he took over, they were in a bad situation and they were able to make a big result."