Southampton's Dejan Lovren and Gaston Ramirez have suffered ankle ligament injuries and are facing several weeks on the sidelines.
The club have confirmed the extent of the damage sustained during Saturday's 2-2 draw with Sunderland at the Stadium of Light, but have refused to comment on the expected recovery time for either player.
The news comes as another blow to manager Mauricio Pochettino, whose executive chairman at Saints, Nicola Cortese, quit the club last week.
Midfielder Ramirez was injured by a nasty-looking Wes Brown challenge at the weekend, only moments before centre back Lovren hurt himself when he tangled with Craig Gardner.
A club statement said: "Saints can confirm that Lovren and Ramírez both suffered ankle ligament injuries. The players are still being assessed, so we are reluctant to place a timescale on when the duo will be able to return to action."
The club, meanwhile, has promoted chief financial officer Gareth Rogers to the role of interim chief executive, following Cortese's exit.
Former Blackburn chairman John Williams had been tipped to succeed Cortese but owner Katharina Liebherr has appointed from within, for now at least.
"I am delighted that Gareth has agreed to step into this role," Liebherr told the Saints' official website.
"After the events of the past week, my priority has been to bring stability to the management of the club and I am pleased that we have been able to make this appointment from within. We had a very positive meeting with all the staff on Monday and I am sure Gareth's appointment will be warmly received."
Liebherr had earlier this week spoken of her desire to restore stability in an open letter to fans.
"Off the pitch, my priority is to establish the proper running of the club at the top," she wrote.
"I have met Pochettino and given him my complete support to build on the good work that has already been achieved.
"We have also said that we have no plans to sell any of the squad during the January transfer window. I met the rest of the staff and gave them the same message of support."