Ross McCormack, James Forrest and Danny Fox have withdrawn from the Scotland squad ahead of the forthcoming World Cup qualifiers against Wales and Serbia, according to the Scottish Football Association's official Twitter account.
Norwich defender Steven Whittaker has been drafted in by Gordon Strachan as he prepares for his first competitive game as national team boss against the Welsh at Hampden on Friday night.
Celtic boss Neil Lennon revealed at the weekend that Forrest would be out with a back injury but the reason for McCormack and Fox's withdrawals are as yet unknown.
Scotland assistant manager Mark McGhee later revealed all three players were likely to be out of the Serbia game as well as the first of the double header against Wales on Friday night.
McCormack, who was sent home because of illness ahead of last month's friendly win over Estonia, missed Leeds' game against Huddersfield on Saturday after suffering a head knock in their previous npower Championship match against Peterborough.
Leeds manager Neil Warnock told his club's official website: "Ross actually wanted to play against Huddersfield on Saturday, and I wanted him to play, but you can't go against the doctor who said it was a very serious situation."
Fox has missed Southampton's last two games after going off with a thigh injury in their defeat by QPR earlier this month. McGhee admitted the loss of Forrest was a "big, big blow".
"I think the manager had hopes he would play, so that's very, very disappointing," McGhee said.
Norwich full-back Whittaker made his first appearance of 2013 on Saturday when he came on as an 89th-minute substitute against Sunderland.
"Gordon spoke to Chris Hughton and Steven and feels he has done enough to be here if he is needed," McGhee said. "We probably feel he hasn't played enough games that he would be in serious contention, but I think he is one the manager feels will be here in the future."