The No.8 and captain has a minor calf issue and as a result head coach Jacques Brunel has opted to leave him out as a precautionary measure.
Brunel has made changes to his side throughout the competition and this time is no different with a new half-back pairing of Tito Tebaldi and Luciano Orquera replacing Edoardo Gori and Tommaso Allan.
Elsewhere, Paul Derbyshire comes in at flanker for the injured Alessandro Zanni while it is Marco Bortolami who replaces Parisse both on the field and as captain with Joshua Furno moving to the flanker and Robert Barbieri moving to No.8.
Brunel was quick to deny however, that he is saving his best for last and for the visit of England to Rome next week.
"With five players unavailable we had to adapt ourselves," he said. "Among the half-backs we wanted to give a chance to those who had played less like (Luciano) Orquera, also because against Scotland we didn't manage the pressure well in our half.
"I wanted to integrate (Tito) Tebaldi into the group before the tournament but he had a slight injury and we couldn't select him.
"The choices made are not in relation to next Saturday's game in Rome against England but based on consistency that we want to have. The next match is against Ireland and we have prepared for the match against that opponent."
Italy picked up a first ever Championship win over Ireland 12 months ago but Brunel is expecting a far sterner challenge a year on in Dublin.
He added: "Ireland is certainly a better squad than last year. But we have to remember that we beat them barely a year ago in Rome and in a rather convincing fashion. We have the chance to do so again."
Ireland meanwhile, make just one change to their side as Peter O'Mahony has failed to shake a hamstring problem, ensuring Iain Henderson gets his second international start.
In better news for Joe Schmidt, Jonathan Sexton is fit to play following a thumb injury while Brian O'Driscoll makes wins his 140th Test cap - a new world record for international appearances - in his final game for Ireland on home soil.
"He's in good shape, he's a good athlete, and we felt he made quite an impact when he came on against England," said Schmidt of 22-year-old Henderson.
"He's got a really good future at both international and the provincial scene.
"There was a decent temptation to make a few more changes.
"We think there are players out there who have earned an opportunity, but we have to balance that with continuity that we've had.
"Some players had a weekend off last week with their provinces, and if they miss two weekends it wouldn't be the best preparation for France.
"I think the team we have selected reflects the respect we have for Italy."