Manchester United winger Nani (hamstring) and central defender Jonny Evans (groin injury) have both been ruled out for Saturday's match against Aston Villa, coach Sir Alex Ferguson said Friday.
The Portugal star suffered the hamstring injury during Wednesday's Champions League 3-1 victory over Braga and is expected to be out 10 days.
Evans' absence will mean a second game in four days for Chris Smalling.
"Jonny is a doubt," said Ferguson. "It is not a serious one. We are monitoring it and hopefully he will be OK."
For Aston Villa, midfielder Karim El Ahmadi will return after a one-match ban. Eric Lichaj is suspended after picking up his fifth yellow card of the campaign during the 1-0 win at Sunderland, Joe Bennett is struggling to overcome a knee injury and Darren Bent is still sidelined by ankle injury.
The Midlands giants were the side United edged out to win their first title of the Ferguson era in 1993. United has not lost at Villa Park since 1995, earning 10 wins and six draws over the past 16 years.
The Red Devils have won 11 more titles, a figure almost matched by Villa's turnover of managers, which, following the summer arrival of Paul Lambert, stands at eight since the exit of Ron Atkinson in 1994.
"It is a daunting task to bring Aston Villa back to where everyone expects them to be," said Ferguson. "They have a great history. They won the European Cup in 1981. It is correct to say they have not matched their expectations over the years.
"You wonder whether changing managers has a bigger impact than the actual playing standards of the team. They have had quite a few managers and it takes time to change a team's fortunes."
Sir Alex Ferguson has confirmed Manchester United skipper Nemanja Vidic is on track to recover from his latest knee operation by Christmas.
The 31-year-old made his comeback from cruciate surgery at the start of the season but within a month was experiencing more discomfort, which condemned Vidic to yet another stint on the sidelines.
United have not exactly been watertight in the Serbian's absence, even if they have climbed to the Premier League summit and booked their place in the Champions League knock-out stages.
However, clearly, the return of one of the world's best defenders would have a positive impact on United's season.
And Ferguson expects to be welcoming his captain back during the packed festive program.
"I think it's Christmas time for Vidic," said Ferguson. "If we get him back for Christmas, then I'll be happy. There's been no setback but we cannot take any chances after his cruciate."