Olympiakos quartet Diogo Figueiras, Seba, Emmanuel Emenike and El Fardou Ben Nabouhane will miss the Champions League clash with Barcelona on Wednesday night (18 October) having been left out of Takis Lemonis' 20-man travelling squad to face the La Liga giants.
However, experienced centre-back Jagos Vukovic returns to the list despite having been out of action since suffering an injury while on international duty earlier in September.
The Piraeus outfit will visit Barcelona having fallen to the bottom of Group D having lost their previous two group matches against Juventus and Sporting Clube de Portugal.
The SuperLeague Greece winners have also endured a difficult start to the domestic campaign, currently sat in fifth place with only 11 points from seven games.
However, they secured an important 4-3 victory at Panionios over the weekend and will be hoping to extend the good run when they visit Barcelona on Wednesday night.
However, manager Lemonis will be missing at least two of his regular starters for the daunting challenge as both right-back Figueiras and winger Seba have failed to make the squad alongside Emenike and Ben Nabouhane.
Figueiras and Seba started and completed the full 90 minutes during the win over Panionios but neither of them have been included in Lemoni's travelling squad to Barcelona.
The absence of the Portuguese defender is a particularly frustrating setback for Olympiakos as he has been a regular presence at right-back since the beginning of the campaign.
Seba, meanwhile, is also a regular in Lemonis' line-up, having already started seven games this season, including in the previous Champions League defeat to Juventus.
Furthermore, summer signing Emenike and Ben Nabouhane also remain on the sidelines having already missed the weekend encounter with Panionios.
Meanwhile, Barcelona returned to training on Monday morning following their 1-1 draw against Atletico Madrid on Saturday.
Ernesto Valverde is not expected to have any fresh injury concerns when he takes on one of his former sides but long-term casualties Ousmane Dembele and Rafinha Alcantara will certainly miss the game.
"Given a day off after the match at the Wanda Metropolitano (1-1), FC Barcelonaplayers returned to work at the Ciutat Esportiva on Monday morning in preparation for Wednesday's Champions League tie against Olympiacos, the third game of the group stage," the La Liga leaders confirmed in its official website.
"Ernesto Valverde's men, who are looking for their third consecutive win in the competition after the victories against Juventus and Sporting, trained on the Tito Vilanova pitch in a session that had all the available first team present as well as Barça B goalkeeper Adrià Ortolá. The team will rest on Monday afternoon before another training session on Tuesday morning."