West Ham pair Andy Carroll and Winston Reid will be out for at least three months after having surgery.
Striker Carroll, 29, has had an operation on his ankle, with New Zealand defender Reid, 30, having surgery on a knee problem.
Ex-Liverpool and Newcastle man Carroll missed three months towards the end of last season with an ankle injury.
"This is a big blow for them and us but we hope to see them back as soon as possible," said boss Manuel Pellegrini.
Reid has made 222 appearances for the club since joining in 2010, while Carroll - who last played for England in 2012 - scored three goals in 18 appearances last season.
Both players have returned early from West Ham's pre-season training camp in Switzerland, with Pellegrini looking to bring in reinforcements to cover their lay-offs.
"It does mean that we have lost two players in key areas, though, and we'll continue to work hard with the owners to make further additions to strengthen the playing squad, beyond the five new signings already confirmed," he added.
Meanwhile, the Hammers have confirmed Argentina midfielder Manuel Lanzini will return to London shortly as he makes "good early progress" from the knee injury which kept him out of the World Cup.