Alun-Wyn Jones becomes Wales 127th captain as head coach Warren Gatland names just two of the forward pack that played in the 21-16 defeat in Paris.
Ospreys lock Jones is joined by Andy Powell at No8, with the six remaining forwards all new inclusions in the starting XV.
Regular Welsh skipper Ryan Jones is named on the bench alongside fellow Lion Gethin Jenkins, while 2001 and 2005 tourist Martyn Williams is rested completely.
In the backs, World Player of the Year Shane Williams and in-form full back Lee Byrne keep their places in the back three, while Jamie Roberts moves from inside to outside centre.
James Hook takes over from Stephen Jones at fly-half, with 2005 Lions Dwayne Peel and Gavin Henson also making their first starts of the championship. Peel and Hook will be renewing a half-back partnership that has not been seen from the start of an international since the clash with South Africa in 2007.
Mark Jones replaces Leigh Halfpenny on the right wing, with Tom Shanklin, another 2005 Lion, making way for Henson and Mike Phillips dropping out for Peel.
"We have made a series of changes with no disrespect to Italy," said Gatland, who will act as forwards coach when the Lions take on the Springboks later this summer.
"If we are to consistently be one of the top four or five teams in the world we need to back the depth in our squad.
"We have made changes but there are arguments to say we are stronger in certain positions.
"If I was playing against Italy I would be excited about both the opportunity which presents itself and, looking around me, about the team which has been selected.
"We have come a long way in the last 12 months and achieved a fantastic amount, but the best teams in the world develop depth of experience in their squad and back themselves.
"The choice of Alun-Wyn as captain next week is an example of us doing exactly that and also looking to the future."
Lee Byrne; Mark Jones, Jamie Roberts, Gavin Henson, Shane Williams; James Hook, Dwayne Peel; John Yapp, Huw Bennett, Rhys Thomas, Luke Charteris, Alun-Wyn Jones (captain), Jonathan Thomas, Dafydd Jones, Andy Powell
Replacements: Matthew Rees, Gethin Jenkins, Bradley Davies, Ryan Jones, Mike Phillips, Stephen Jones, Tom Shanklin