O'Shea was due to fly to North America with his team-mates this afternoon, but left the camp after learning of a family bereavement.
A spokesman for the Football Association of Ireland confirmed the Sunderland ace was out of the squad.
The spokesman said: "The FAI, the Irish team management, backroom team and players all offer their sincere condolences to John O'Shea on the death of his Uncle, Jimmy O'Leary, in Waterford this morning."
O'Shea is one of nine members of the squad who will not make the trip.
Shane Long and Aiden McGeady are excused because they are getting married, Marc Wilson is scheduled to undergo surgery to remove a metal plate from his leg, Glenn Whelan is rested and Keiren Westwood, Wes Hoolahan and Jon Walters are injured.