Ireland skipper Brian O'Driscoll has failed to recover from his hamstring strain and will miss Sunday's RBS 6 Nations clash with France at Croke Park.
Shane Horgan will replace O'Driscoll in midfield with Geordan Murphy promoted from the bench to the right wing. Andrew Trimble fills the vacancy among the substitutes.
In another blow to Ireland's hopes of toppling France, veteran Munster scrum-half Peter Stringer has been ruled out with his fractured hand.
Ulster half-back Isaac Boss takes the number nine jersey in Stringer's absence with Eoin Reddan of Wasps plugging the gap on the bench.
O'Driscoll suffered his hamstring strain in last Sunday's 19-9 victory over Wales and rated his chances of making the Croke Park opener as 50-50.
But Ireland head coach Eddie O'Sullivan revealed the France game had come too early for his captain.
"Brian was close to being fit but felt a tightening of the hamstring," said O'Sullivan.
"Emotionally pulling him out was a difficult decision to make, but it was an easy one from a practical point of view."
O'Driscoll's loss represents a huge blow to Irish hopes, but the pain has been tempered by the return of Horgan ahead of schedule.
Horgan, in magnificent form during the autumn, was expected to be back from a knee injury in time to face England on February 24 but has made a full recovery ahead of schedule.
"Shane has trained well all week and has taken hits on the knee that was injured," said O'Sullivan.
Stringer's experience will be missed against the Six Nations champions. But O'Sullivan is confident Boss, who made his full debut against Australia in the autumn, will acquit himself well.
"Isaac Boss will bring a different sniping game to Stringer - but after his performances in the autumn, I have no worries about him," he said.
There are no changes to the pack with number eight Denis Leamy able to play, despite having an abscess incised and drained on Monday.