Aymeric Laporte is expected to be out for some time after having successful surgery on an injured knee - and it leaves boss Pep Guardiola with a selection headache as he plans Manchester City's title defence.
The centre-back damaged cartilage and his lateral meniscus against Brighton last weekend and joins John Stones, who has a thigh problem, in the treatment room.
This leaves the champions with just one fit senior central defender in Nicolas Otamendi.
After Vincent Kompany left in the summer and the failure to land Harry Maguire, whose valuation they were not prepared to meet, City cannot sign another centre-half until the January transfer window, by which time they will have played another 17 Premier League games.
So how much will City miss him?
Premier League managers usually go into the international break with trepidation about their players returning injured, but in the case of Laporte that has already happened and just days after Guardiola had hailed the player's long-overdue call-up to the France squad.
Guardiola expressed just last week how happy and grateful he was to Didier Deschamps for choosing to select the player he regards as "the best left-sided central defender in Europe".
Laporte has become arguably Manchester City's first name on the team sheet, having starting 49 matches in all competitions last season - more than any of their other outfield players.
As he thrived last term, City conceded just 23 Premier League goals and his calmness on the ball and range of passing often sees him take the starting point for City attacks. So his absence leaves a big hole.
This is even more the case because he is also a threat in the opposition box, scoring five goals last term including one against Brighton on the final day as they wrapped up the title.
What are City's options to replace him?
Currently Otamendi is the only fully-fit central defender so he appears certain to start when the Premier League resumes after the international break and City travel to newly-promoted Norwich in nine days' time.
Stones is not with the England squad as he recovers from the injury that has kept him out of City's last three matches, but he is back in training and Guardiola confirmed last week, that barring any set-backs, he will be fit for the trip to Carrow Road.
But should he suffer a set-back, experienced midfielder Fernandinho may well drop to centre-back, having replaced Laporte when he was stretchered off against Brighton.
Although it has been a plan for him to play more matches at centre-half, it's doubtful Guardiola was expecting to rely on a defensive midfielder outside of rotation - and so early in the season.
Fernandinho played two matches out of his usual position last season with mixed success, firstly authoritatively marshalling the City defence in a 3-1 win against Arsenal in the Premier League. But then 16 days later he struggled in Schalke when he was panicked into giving away a penalty, which not only earned him a yellow card but also a suspension for the second leg.
So aside from Fernandinho, options become very limited. Guardiola has been impressed by the development of young Spanish defender Eric Garcia and in pre-season he was promised increased game-time during this campaign.
But it would be a big step up for the 18-year-old, whose only first-team appearances so far have come in the Carabao Cup, including both legs of last season's semi-final win over Burton and the quarter-final against Leicester.
But then there is Kyle Walker. Guardiola confirmed after Laporte's injury that "if one day I need to put Kyle Walker as a central defender, he is going to play there" - and he also backed the player to play at centre-back for England at last year's World Cup.
That, however, was on the right of a back-three and it would be a big risk to move him to centre-back in a two, given that he is so untested in partnership with one other, which Guardiola currently favours.