Michael Carrick, Phil Jones and Marcos Rojo will miss Manchester United's visit to Everton on 26 April, manager Louis van Gaal has confirmed.
Daley Blind also remains a doubt having missed the 1-0 defeat to Chelsea on 19 April, suggesting Wayne Rooney will likely be deployed in a holding midfield role at Goodison Park.
While he has remained on the periphery of Van Gaal's squad throughout the second half of the season, Rafael da Silva will have no further role to play in the club's remaining five games, having suffered a broken rib while playing for the club's Under-21 ranks on 20 April.
Adnan Januzaj was another casualty in that game but Van Gaal described his injury as "not so heavy" during his pre-match press conference.
Jones is another to have fallen victim of United's fresh spate of injuries in recent weeks. He was one of four players to emerge from the 4-2 victory over Manchester City with a knock that ruled him out of the trip to Stamford Bridge.
With both he and Rojo unavailable, Van Gaal faces another selection dilemma at the back. Jonny Evans is once again back in contention having served a six-match ban for spitting at Newcastle's Papiss Cisse. But Paddy McNair's excellent performance alongside Chris Smalling against Chelsea could see the manager opt for the same back four.
Robin van Persie is another in line for his return to the first team after regained his full fitness. The Dutchman returned to first-team training earlier in April and featured for the Under-21s on Monday. He is likely to challenge Radamel Falcao for a role up front.
"Yes, he has to train very hard, play in the second team," Van Gaal said. "He has to show his qualities again. Then I have to compare him with the positions he can play, with the players that play in that position - it is always the same."