Manchester United captain Harry Maguire has been ruled out for Wednesday's Champions League match against Villarreal and could miss "a few weeks" of action with a calf injury.
Maguire and fellow defender Luke Shaw both suffered injuries in the disappointing 1-0 Premier League defeat to Aston Villa last time out.
And manager Ole Gunnar Solskjaer revealed the centre-back is set for a spell on the sidelines.
But he had more positive news on Shaw, who is in contention to face the Spanish side and does not look poised for a long spell out regardless of whether he is able to start the match at Old Trafford.
"Luke has been in on Tuesday, so I will give him a chance to be involved," Solskjaer said at his pre-match news conference.
"He did not train with the team [but] hopefully Luke can be involved.
"Harry is more or less definitely out, it doesn't look good. It is his calf, that might take a few weeks.
"Let's see how quickly he recovers. He wanted to play against Villarreal, he missed the last game [against them in the Europa League final]."
With Aaron Wan-Bissaka already suspended after a red card in the opening Group F defeat against Young Boys, United could be forced to change three members of their regular back four alongside Raphael Varane.
Victor Lindelof, Eric Bailly, Diogo Dalot and Alex Telles are among the candidates to come into the starting XI.
Solskjaer added: "We will have to make a few changes. You always look at the opposition and sometimes you need to make adjustments.
"But we look at ourselves mostly. The more injuries you get, you might need to do tactical changes. I have got Eric, Rapha, Victor. Alex and Diogo 100 per cent fit."
— UEFA Champions League (@ChampionsLeague) September 28, 2021
The last five meetings in European competition between United and Villarreal have all ended in draws.
Four of those encounters were goalless, the exception being the 2021 Europa League final, which Villarreal won 11-10 on penalties after a 1-1 draw.
"You expect what you have learned in the last few seasons," added Solskjaer. "We have played each other five times, every time has been a draw.
"They are very well organised, technically very good. They can play from the back. It is hard to press against them, which I thought we did well in the final.
"Difficult to create chances against and we have to be better to create chances. It was an even final."
United go into the key game looking to end an unwelcome trend.
They are winless in their last seven matches against Spanish teams in the Champions League (D3 L4), with their last such victory coming against Real Sociedad back in October 2013 (1-0).