Manchester United's Chris Smalling is out for 10 weeks after undergoing surgery for a broken metatarsal.
Smalling, 22, missed the end of last season with a groin problem that ruled him out of Euro 2012 and the Olympics.
Although the defender was absent from United's pre-season tour, manager Sir Alex Ferguson had expected him to be fit for the start of the campaign.
"It is a bad blow for the boy. He is only 22, he is young. Hopefully he gets over it," said Ferguson.
The absence of Smalling, who was injured in training on Wednesday, puts further pressure on Ferguson's defensive resources ahead of United's first Premier League game at Everton on 20 August.
Jonny Evans is doubtful for start of the season with an ankle injury and captain Nemanja Vidic is working his way back to fitness after a serious knee problem.
Ferguson expects Vidic to be ready for the start of the campaign, with Rio Ferdinand and Phil Jones his only other senior centre-back options.
Smalling, who was signed from Fulham in a £10m deal in 2010, made 14 Premier League starts last season.