Sheffield United defender Lecsinel Jean-Francois is to have knee surgery and will be out for up to two months.
The 26-year-old played for 15 minutes as a substitute in the recent JP Trophy win over Notts County after recovering from a long-term knee injury.
But boss Danny Wilson told BBC Radio Sheffield the Haiti international hurt his other knee and now needs an operation on a cartilage problem.
"All the bad luck he's having, we're absolutely gutted for him," he said.
"From such an innocuous collision, he ends up with a two-month setback.
"Sadly, he's going to have to go back to the drawing board and start again."
Meanwhile, Wilson is concerned about the goalkeeping situation at Bramall Lane.
Youngsters George Long and George Willis are the only keepers currently available after first-choice Mark Howard suffered a thigh injury earlier this month that is likely to keep him out for up to 12 weeks.
Wilson was hoping to tie up a deal for former Wales international Danny Coyne, who is a free agent after being released by Middlesbrough in the summer, but does not now expect it to go ahead because of financial constraints.
"You've got to give the young lads their head at times and you don't know until you try them.
"We were always going to give George (Long) a run and whoever does come in will be sat on the bench.
"We do need that cover but it's not going to happen unless someone goes out of the club," he admitted.
"We've known about the situation at the club for a long time. This is a key area but it doesn't change the opinion of the board - to bring people in, we have to let people go out."