Ulster outside-half Humphreys had an outstanding game in the RBS 6 Nations opener against Scotland last Sunday, scoring 26 points as the Irish scored a 36-6 win in Edinburgh - their first at Murrayfield since 1985.
O'Gara missed last weekend's match with an ankle injury but had since recovered and Ireland coach Eddie O'Sullivan was considered recalling the Munsterman, who had been his first-choice at number 10 this season.
Then O'Gara suffered a reaction to the injury and a specialist ruled him out of contention, leaving Humphreys to win his 49th cap at the weekend. Harlequins' Paul Burke retains his place on the bench.
Leicester star Geordan Murphy is the only change from the team which beat Scotland, replacing Shane Horgan on the right wing, having come on for the Leinster man early on against the Scots and scoring a second-half breakaway try.
Yet he could start at full-back in Rome as Girvan Dempsey has been struggling with a groin strain. He has been with the proviso that Murphy will step in at number 15 should he fail to pass a fitness test. That would mean John Kelly filling in on the wing.
Elsewhere, centre Rob Henderson is promoted to the bench after completing his comeback from injury in the 'A' side which drew with Scotland last week in Stirling.
Ireland team to play Italy in the Stadio Flaminio:
Backs: G Dempsey (Terenure)/G Murphy (Leicester); G Murphy (Leicester)/J Kelly (Cork Constitution), B O'Driscoll (Blackrock); K Maggs (Bath), D Hickie (St Mary's), D Humphreys (Dungannon), P Stringer (Shannon).
Forwards: R Corrigan (Greystones), S Byrne (Blackrock), J Hayes (Shannon), G Longwell (Ballymena), M O'Kelly (St Mary's), V Costello (St Mary's), K Gleeson (St Mary's), A Foley (Shannon).
Replacements: F Sheahan (Cork Constitution), M Horan (Shannon), L Cullen (Blackrock), A Quinlan (Shannon), G Easterby (Llanelli), P Burke (Harlequins), R Henderson (Young Munster)