O'Brien has withdrawn as he battles a persistent issue, reducing Martin O'Neill's party for the upcoming clashes against Oman and Georgia to 26.
The Football Association of Ireland confirmed the news, posting on their official Twitter account that the defender would return to West Ham.
"Joey O'Brien has withdrawn from the Irish squad, and will return to his club for treatment on an ongoing knee injury," the Tweet read.
O'Neill has picked a big squad ahead of the nation's first Euro 2016 qualifier in Georgia on Sunday.
First comes a friendly against Oman on Wednesday, though, as Ireland look to break a run of six matches without a win.
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