Everton centre-back pair Jarrad Branthwaite and Mason Holgate will miss Saturday's clash with West Bromwich Albion at Goodison Park (12.30pm), but Alex Iwobi is back in contention after recovering from a knock which kept him out of the Blues' victories over Spurs and Salford City.
Speaking at his pre-match press conference, manager Carlo Ancelotti confirmed Branthwaite and Holgate were both unavailable for the game along with long-term absentees Jean-Philippe Gbamin (Achilles) and Cenk Tosun (ACL).
Defender Branthwaite sustained an ankle injury during Everton's 3-0 win over Salford on Wednesday night and the 18-year-old is expected to be unavailable "for three to five weeks".
Holgate, meanwhile, continues to be sidelined with a toe injury and Everton boss Ancelotti said the Club could enter the transfer market to boost their centre-back options.
The Blues have already signed four players this summer - Niels Nkounkou, Allan, James Rodriguez and Abdoulaye Doucoure.
"Jarrad has a problem with his ankle," said Ancelotti. "He doesn’t need surgery but will need to rest for around one month.
"With Mason, we have to follow the advice of the doctors and medical staff. He is out for two or three months.
"But, honestly, he feels good at the moment. He is walking in the swimming pool without any problem
"The other players are fit and ready to play."
He added: "We are looking for a centre-back, if the [transfer] market offers something."
Everton captain Seamus Coleman is line to make his 250th Premier League start in Saturday's game at Goodison.
Manager Ancelotti said the 31-year-old Irishman's longevity is testament to his exemplary professionalism - and is confident the right-back can perform at the highest level for many seasons to come.
"Seamus will start tomorrow, so congratulations to him," Ancelotti said.
"It is a great achievement [to start 250 Premier League games] and we are honoured to have him as a captain in this team.
"Seamus can play until he is 40! He is still young."
Everton's convincing win over Salford saw Academy graduate Jonjoe Kenny step in for Coleman at right-back.
The defender made 34 appearances on loan at Schalke 04 last season and Ancelotti is convinced Kenny's time in Germany has elevated his all-round game.
"The experience he had in the Bundesliga was very useful for him," the Italian said.
"He is a better player and I have confidence he can play.
"He showed against Salford he can play in the First Team without any problem."