Sam Tomkins and captain Sean O'Loughlin have been ruled out of Wigan Warriors' play-off semi-final showdown with Hull FC on Friday.
A foot injury rules full-back Tomkins out of any possible Grand Final appearance, while O'Loughlin's chances of playing again this season were rated as highly doubtful.
Chairman Ian Lenagan told the club's official website: "This season has thrown up bigger challenges with injuries than ever before, yet I'm proud to say we are still fighting fiercely and successfully as shown by the 12-man victory over Warrington last week and in Friday's performance against Catalans to qualify for a home semi-final.
"Currently, Wigan have only 20 players available from a first-team squad of 35, but there is a tremendous spirit and confidence among this Wigan group that thrives in adversity.
"That character and resilience, plus the ever-improving performances in defence - and growing effectiveness in attack - of our remaining first-team and academy players lays a great platform for the crucial next two weeks.
"Despite all of the challenges that the club have faced this year I, Shaun Wane, Kris Radlinski and the first-team squad believe that we can defy the odds to make this an excellent season-end for Wigan."
Wigan, who lost the 2015 Grand Final to Leeds Rhinos, are also without forward Ben Flower for the semi-final as he serves the second of a two-match ban.