James Tomkins has undergone surgery on his dislocated shoulder, although West Ham hope the defender will be back before the end of the season.
The 25-year-old, who recently signed a new, long-term contract with the Hammers, sustained the injury during a training session last week.
Tomkins' presence was certainly missed in Saturday's 3-0 defeat at Arsenal, where midfielder Cheikhou Kouyate had to play at the heart of defence with Winston Reid also absent.
Stijn Vandenbroucke, West Ham's head of medical and sports science, suggests the New Zealand defender is again unlikely to be available when Sunderland visit this weekend, while also confirming Tomkins and young defender Doneil Henry have gone under the knife
"Unfortunately, we have had two setbacks in the defence," he said.
"James Tomkins underwent successful surgery on his dislocated shoulder on Wednesday and will now commence his rehabilitation, with a view to him returning to fitness before the end of the season.
"Doneil Henry injured his hamstring during his loan spell with Blackburn Rovers and, after consulting with a specialist, he will have an operation at the end of the week.
"Winston Reid is recovering and rehabbing well from the hamstring injury he suffered against Chelsea on 4 March. He is working hard on his fitness and is getting closer to a return."
The trio form part of an injury list which still includes forwards Andy Carroll and Enner Valencia.
Carroll's rehabilitation is going well, says Vandenbroucke, and the England forward "no longer needs crutches to walk and now only has a brace on the knee".
Valencia is on schedule to return after the international break after cutting his toe on a broken mug, while fellow forward Carlton Cole is back in contention after recovering from the hamstring injury sustained at Tottenham last month.
There is also positive news in regards to goalkeeper Adrian, who played the full 90 minutes against Arsenal despite dislocating his finger before the match.
"Although Adrian dislocated his finger in the warm-up ahead of the Arsenal game at the weekend, he had it put back in and taped up by physiotherapist Dominic Rogan before the game," Vandenbroucke told the club's official website, www.whufc.com,
"Adrian played through the pain, which is not to be underestimated, and he too will be available to face Sunderland.
"Adrian avoided a fracture and ligament damage, so he has been receiving treatment by wearing a brace during the night this week to ensure his finger remains pointing in the right direction!
"He was held out of one training session as a precaution but he will be ready to play on Saturday."