With Llanelli pivot Stephen Jones ruled out of the first few rounds of the championship with a broken thumb, Harris is set to be handed the No 10 jersey by coach Steve Hansen and told to run the show.
**Who should start... Iestyn or Ceri?
Eighteen months on from his Â£1m transfer from Leeds to Cardiff, it is make or break time for the former rugby league wonder kid.
"Everyone in rugby league is backing Iestyn to do well. We'd all love to see him back in the 13-a-side game, but not until he has made a success of himself in union," said Harris' former Wales team manager Mike Nicholas.
"I remember picking him for Wales to face the world champion Kangaroos when he was only 18 and not worrying about how he would get on. The bigger the stage, and the greater the pressure, the more Iestyn comes into his own.
"We all know what a world class player he was in league and now all we want is for him to show that form for Wales in the Six Nations.
"It is time he proved to everyone what he can do as a union player and I'm backing him to make a success of his latest opportunity."
Harris is lined-up to partner Dwayne Peel at half-back for Wales with Pontypridd rookie Ceri Sweeney getting his chance on the replacements bench. Harris' experience, and proven goalkicking qualities, will earn him the nod for Stadio Flaminio.
"Iestyn has been involved in big time sport in rugby league and he won't be bothered by the fuss that comes with the Six Nations," said Hansen.
"He's a strong boy, a good running player and a very good goalkicker. His general kicking game is just starting to come.
"Ceri's goalkicking is unqualified because he hasn't kicked at this level before, but he is a good runner and, like Iestyn, has good vision and distribution skills."
Harris has only started two games for Wales at outside half in his 10 Tests - the last ending in a 50-10 home defeat by England in the 2002 Six Nations..
But Saturday's championship opener could be his big chance to prove to the Welsh nation, and the world of rugby league, that he can make it at the highest level in the 15--a-side code.
Italian coach John Kirwan has also hit trouble with his No 10s. Ramiro Pez damaged ankle ligaments in Saturday's warm-up game against a Rest of the World XV and Kirwan has asked Diego Dominguez to fly from Paris to Rome this week to act as cover.
The 36-year-old Dominguez scored 15 points for Stade Francais in a French championship match last weekend after missing the past three weeks with concussion. He originally said he didn't want to be considered for the opening two Six Nations games, but could now find himself back in at the deep end
Meet the Italians: Mauro Bergamasco