England are the only remaining unbeaten side in this year's RBS 6 Nations, while realistically the only sides capable of overhauling Lancaster's men to this year's title meet in Murrayfield this weekend - Scotland and Wales.
England disposed of Scotland 38-18 in the opening weekend of the Championship, before grinding out a 12-6 win over Ireland in Dublin and a 23-13 victory over France at Twickenham last time out.
Lancaster has made five changes to the side that disposed of les Bleus with Toby Flood coming in at fly-half for Owen Farrell, who limped off against France, at fly-half.
Joining him in the half-backs is Danny Care while Mako Vunipola earns his first start at prop, Tom Youngs replaces Dylan Hartley at hooker and James Haskell comes into the side at blindside flanker in place of Courtney Lawes.
"We were very happy with the way we finished the France game," said Lancaster, who also named Tom Croft on the bench - the first time the Leicester Tigers has featured in the matchday squad since recovering from a broken neck.
"The impact the replacements made shows that we have competition for places across the board and we have had to make some tight calls.
"Italy will be highly motivated for this game and we will have to perform for the full 80 minutes. I am sure those starting will seize their chance and the bench will also have a significant part to play as the game goes on.
"The support at Twickenham for the Scotland and France games was superb and I am sure the atmosphere will be fantastic again for our final home match of the Championship."
After a magnificent 23-18 win against France in their opening fixture, Italy have been unable to reproduce the goods as they stumbled to a heavy defeat against Scotland in Murrayfield and were then comprehensively beaten by Wales in Rome last time.
Leicester prop Martin Castrogiovanni was hugely disappointed with his forward's performance in the 26-9 loss against Wales, describing nine of the points coming from poor work at scrum time.
As a result, head coach Jacques Brunel rings the changes to his side, welcoming back captain Sergio Parisse.
Elsewhere, Robert Barbieri comes into the back row while Alberto de Marchi gets the nod at loosehead prop and Joshua Furno and Quintin Geldenhuys form an all new second row.
In the backs, Gonzalo Canale moves out one to outside centre as Gonzalo Garcia comes in for Tommaso Benvenuti while Luciano Orquera replaces Kristopher Burton at fly-half.
There's no doubting England are the overwhelming favourites to beat Italy this weekend - but Castrogiovanni has promised a big improvement upfront.
"We conceded nine points from scrums, which is my problem as well as the team," said Castrogiovanni.
"I need to work on that. The referee is always right. If we had done what we were told and also managed our kicking game better, maybe the referee wouldn't have mattered so much against Wales.
"There are no excuses. You need to be perfect in all aspects but we weren't.
"I was very honoured to be made captain, but I don't like losing. I hate losing even when I am playing PlayStation.
"We didn't really handle some areas very well against Wales. There are ups and down in life, and this was one of the downs."