Prop Gethin Jenkins takes over as skipper from flanker Warburton, who has a knee problem, with Ospreys openside Justin Tipuric packing down in the back-row alongside Dan Lydiate and Toby Faletau.
The highly-rated Tipuric, 22, makes his first Wales start, with Warburton ruled out.
Warburton did not play against Scotland last month because of a thigh injury that forced him off at half-time in Dublin the previous weekend.
And Wales coach Warren Gatland has clearly decided to take no chances with his World Cup leader ahead of a potential Six Nations title decider and Grand Slam game against France on Saturday week.
Gatland has made one other change from the side that beat England at Twickenham 10 days ago, recalling fit-again hooker Matthew Rees instead of Ken Owens.
Rees' return means Gatland can field the 2009 British and Irish Lions Test front-row of Jenkins, Rees and Adam Jones.
Former Wales captain Rees missed the World Cup due to a neck complaint, while a calf muscle strain hampered him during the early part of Wales' Six Nations campaign.
Centre Jamie Roberts, meanwhile, takes his place in midfield after recovering from a knee injury, allowing Gatland to name an unchanged back division for the fourth successive game.
And there is a notable addition to the bench, with World Cup lock Luke Charteris providing second-row cover.
Charteris has played just one game - for Newport Gwent Dragons against Munster three days ago - since undergoing wrist surgery after the World Cup.
Three changes on the bench see Charteris replace Tipuric, Owens taking over from Richard Hibbard and James Hook, fit again following a bout of chickenpox, in for Stephen Jones.
Gatland said: "Due to injuries to all three players at one time or another, we have not been able to field this 2009 Lions front-row too often.
"So, although we are more than happy with the job Ken has done for us, we are giving Matthew the opportunity make his contribution as the competition reaches its climax.
"We are back at the Millennium Stadium in front of our home fans, and we need to refocus sharply after our Triple Crown triumph at Twickenham if we are to give ourselves the best chance of being in contention for the championship going into that final weekend against France.
"Italy will be hoping to find us complacent, and with one eye on the French game.
"But nothing less than victory on Saturday will be accepted by this Wales team or satisfy the nation behind us, and all of that leaves the players themselves brimming with ruthless intent."
Victory for Wales over Italy - they have never lost to the Azzurri in Cardiff - would leave them needing to beat France at home to secure a second Six Nations title and Grand Slam of Gatland's four-year reign.
Wales team to play Italy: L Halfpenny (Cardiff Blues); A Cuthbert (Cardiff Blues), J Davies (Scarlets), J Roberts (Cardiff Blues), G North (Scarlets); R Priestland (Scarlets), M Phillips (Bayonne); G Jenkins (Cardiff Blues, capt), M Rees (Scarlets), A Jones (Ospreys), A-W Jones (Ospreys), I Evans (Ospreys), D Lydiate (Newport Gwent Dragons), J Tipuric (Ospreys), T Faletau (Newport Gwent Dragons).
Replacements: K Owens (Scarlets), P James (Ospreys) L Charteris (Newport Gwent Dragons), R Jones (Ospreys), L Williams (Cardiff Blues), J Hook (Perpignan), S Williams (Scarlets).
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