Midfielder Ferrie Bodde has been ruled out for the rest of the season after rupturing a cruciate ligament in his left knee for a second time.
The £5m-rated Dutchman, 27, lasted just eight minutes of Saturday's 2-1 win over Sheffield United after he felt something "click".
It was Bodde's first start since suffering the original injury to his knee 10 months ago.
"The replacement graft has ruptured," said Swansea physio Cerian Parham.
"It's very rare for this to happen as the graft is normally stronger than the original ligament.''
Highly influential Bodde, who has also torn a cartilage, was in fine form when the original knee injury struck in the 3-2 home defeat to Birmingham last November.
Despite not playing since then, he was the subject of two bids worth up to £4.5m from Wigan in the summer which was turned down along with a lesser offer from Bolton.
But he made his long-awaited comeback playing 21 minutes as a substitute in the 0-0 draw with Bristol City 10 days before Sheffield United's visit.
Then last weekend, he played 22 minutes in the 0-0 draw at Barnsley, again as a substitute.
Swansea chairman Huw Jenkins has vowed to stand by Bodde during his latest setback.
"It's a big blow, not just for the football club but, more importantly, for Ferrie himself," said Jenkins.
"He is devastated at the moment. But as a club we have told him we will look after him and stand by him every step of the way - as we did last time.
"He will remain a very important member of this football club.
"We all feel for him, and I'm sure every Swans fan will join me
in wishing him a speedy recovery."
Bodde joined Swansea in the summer of 2007 for £80,000 from ADO Den Haag and was instrumental in the heart of midfield as the Swans won the League One title.
He was the subject of two failed bids from Derby County the following summer, before signing a new contract.
And he started last season in fine form before it was ended abruptly against Birmingham.
It is the latest blow for manager Paulo Sousa who has suffered with numerous injuries in midfield.
Darren Pratley has missed the start of the season with a shoulder injury and mumps, while Joe Allen has missed most of the season with a hamstring injury.
Andrea Orlandi is suffering with a thigh strain, Leon Britton picked up a toe injury and Cedric van der Gun has suffered with a thigh problem.
Tom Butler is on his way back though after recovering from a hernia operation and scoring the winner on Saturday.