Everton will be unable to call on centre-backs Ramiro Funes Mori, Phil Jagielka or Michael Keane for their Europa League clash against Apollon Limassol.
In fact, the latter two are struggling to even be fit for Sundayâ€™s Premier League match against Burnley.
It leaves manager Ronald Koeman with a growing injury list and he is short of central defenders.
Ross Barkley, Yannick Bolasie, Seamus Coleman and James McCarthy are also unavailable.
Koeman issued an update of the teamâ€™s injury problems prior to the match.
â€œNo, maybe yes for the weekend but still Michael Keane and Phil Jagielka are not available for Thursday and they are doubtful for the weekend,â€ he told the clubâ€™s official website.
â€œThe rest is the same list not available for tomorrow.â€
Injuries have dogged Evertonâ€™s early season, which has been characterised by inconsistency.
Despite spending around Â£133 million on new players over the summer, Koemanâ€™s side has disappointed, leading to some speculation that his job may be on the line.
Further spending may follow, with the club recently being linked with a move for Paris Saint-Germain forward Edinson Cavani.
On the field, they recently arrested a run of four consecutive defeats with a 3-0 EFL Cup win over Sunderland and a 2-1 Premier League victory over Bournemouth.
That should give the side some confidence going into the match at Goodison Park.
Their Cypriot opponents held last seasonâ€™s semi-finalists Lyon to a 1-1 draw in their first Europa League outing and will be no pushovers.
Everton need to produce a big improvement on the performance they offered during a 3-0 defeat to Atalanta that has put them on the back foot in the group.
Keane and Jagielka partnered each other at the back in that match, but Koeman has little choice but to field Mason Holgate and Ashley Williams against Limassol.
They played in central defence against Bournemouth and with no other fit centre-backs available, the managerâ€™s choices are limited.
He does at least have more options in midfield and up front, where he has almost a clean bill of health.
Following his two-goal performance from the bench against the Cherries, Koeman may be tempted to give Oumar Niasse a start.
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However, given that he also came off the bench to score against Sunderland, the Senegalese may be asked to reprise that role again if Koeman wants to continue with Dominic Calvert-Lewin leading the line.