Jamie Heaslip has lost his battle for fitness ahead of the Six Nations opener against Italy in Rome while Munster out-half Ian Keatley is preferred to Ian Madigan at out-half.
Jordi Murphy takes the place of his provincial team-mate at number 8 with Munster's Tommy O'Donnell named among the replacements.
Heaslip's absence is tempered somewhat by the return of Sean O'Brien, who will make his first international appearance since the 2014 Autumn international defeat to New Zealand. The powerful backrower made his comeback from a second shoulder reconstruction in 12 months when playing for 50 minutes for the Ireland Wolfhounds last Friday
Ian Madigan will have to make do with a place on the bench, while Kieran Marmion has been left out of the match-day squad with Isaac Boss preferred as cover for Conor Murray.
Jared Payne and Robbie Henshaw resume their midfield partnership, while up front, Schmidt has decided to keep faith in Mike Ross despite the tighthead being left out in the cold by Leinster coach Matt O'Connor who has favoured Marty Moore, in recent weeks. The young prop is named on the bench.
Devin Toner and captain Paul O'Connell remain the preferred choice at second-row, while Heaslip's injury has forced a rethink at the back of the scrum with Peter O'Mahony joining O'Brien and Murphy.
Simon Zebo holds on to the No 11 jersey despite the return of Dave Kearney, Keith Earls and Luke Fitzgerald to fitness.
Schmidt revealed experienced back-rower Heaslip regained full fitness on Thursday, but Ireland's coaches chose not to risk him against the Italians.
Ireland's head coach confirmed Heaslip's absence led to the decision to hand O'Brien a start rather than a seat on the bench.
"Jamie trained fully today, if that had been the case on Tuesday the decision might have been different," said Schmidt.
"He's 100 per cent fit now, he will train fully next week and that will allow him to focus on the France game.
"His powers of recuperation are second to none, but we just decided to be conservative with it.
"What we're missing is a lot of experience, but Peter O'Mahony has that, he's a leader of his provincial team and of our group.
"Jordi (Murphy) has had a really solid season since Christmas.
"We certainly didn't necessarily see Sean (O'Brien) starting this week but we felt he did well in the Wolfhounds game.
"There's always a degree of risk with players coming off the bench after returning from injury.
"If Sean can give us a great 50 to 60 minutes I think that will help put us into the game hopefully.
"Jordi has played a lot at number eight.
"It's not something he's played massively recently, but he has covered for Jamie in recent years until Jack Conan has emerged.
"I think Jordi is a pretty good fit in the circumstances."
Schmidt backed experienced tighthead Ross to contain Italy's renowned front-row in the scrum despite losing his club place to Moore at Leinster in recent weeks.
The Kiwi coach said Ross will be unfazed by any lack of action, especially after shaking off that groin issue for the autumn Tests.
"There was a degree of confidence to select him this time because he came in off minimal game time in November and did a job," said Schmidt.
"He's in far better condition than that now so we feel he can do a job.
"I think our scrum was a real strong point for us in the last Six Nations.
"The personnel haven't changed too much, and Mike did really well last week against Matt Mullan for the Wolfhounds.
"So I think Mike's in a pretty good place to be honest."
Ireland team v Italy: R Kearney; T Bowe, J Payne, R Henshaw, S Zebo; I Keatley, C Murray; J McGrath, R Best, M Ross; D Toner, P O'Connell (capt); P O'Mahony, S O'Brien, J Murphy.
Reps: S Cronin, J Cronin, M Moore, I Henderson, Tommy O'Donnell, Isaac Boss, I Madigan, F Jones.