West Ham duo Winston Reid and Victor Moses have been ruled out until the New Year with hamstring injuries.
Reid, 27, was injured in training on Wednesday and could be set for a long spell out, with the results of a scan expected on Friday.
On-loan Chelsea winger Moses picked up his injury in Saturday's 0-0 draw at Manchester United, and manager Slaven Bilic has ruled him out for four to six weeks.
They are the latest additions to a growing casualty list at Upton Park which threatens to derail their fine start to the season.
The Hammers have already lost Dimitri Payet and Diafra Sakho until February, while Manuel Lanzini is out for six weeks with a thigh problem suffered in training.
Enner Valencia has been out for five weeks with an ankle injury but he could give Bilic a boost by being added to the squad to face Stoke on Saturday.
Bilic said: "Reid got injured in training, it doesn't look good. It's one of those they tell you is four to six weeks but it doesn't look like a small one. He slipped and felt it rupture.
"Victor is out for four to six weeks. It's a blow, we have had six injuries since the Everton game. Before that we had a full squad, then Payet and Valencia were injured against Everton and now we have four muscle injuries.
"I am hoping Lanzini will be back for the Swansea game. Payet and Valencia are also looking good, we will have to wait and see."
Bilic lamented the Hammers' growing injury list, but called on the fit players in his squad to stick together and cover the absences.
"We are now missing six very important players, but we can't complain," he said. "We need to get over it and do well with the players we do have.
"We have a very good medical team here so hopefully some players will come back quicker than first expected. Of course it will be difficult without players like Lanzini, Payet and Sakho, but we played without all of them at Manchester United.
"Now it is about the squad and the character of the players we have, it is time for them to step up and help the team."
The coach also confirmed that the Hammers will switch training grounds sooner than intended due to concerns over the pitch, but does not believe the recent injury problems are down to either his ground staff or medical team.
"We were planning on moving the training ground to Rush Green at the end of the season; now we are moving that forward," he said.
"We will be training at Rush Green from Monday. The pitches here at Chadwell Heath are soft on top but hard underneath, which is the worst combination. So I have made the decision to go to Rush Green where the pitches are better.
"This is not the fault of the groundsmen or the medical staff; it is just a fact. The season is very long, every team has good luck and bad luck with injuries. I am optimistic that we will manage."
Bilic hinted he could add to his squad in January if the right players become available, adding: "There is always room at every club for exceptional players to come in.
"We will have to see what the situation is in January."