De Luca was a late withdrawal from the 32-14 loss to Ireland last Saturday after exacerbating a hamstring problem in the warm-up and comes in for wing Lee Jones, who suffered severe concussion in the defeat in Dublin.
Max Evans, who took De Luca's place in the team at the Aviva Stadium, has taken Jones' slot on the right wing.
The only other change in personnel in the matchday 22 sees Bath back Jack Cuthbert named among the replacements.
Head coach Andy Robinson has 11 losses from 14 Six Nations matches after defeats to England, Wales, France and Ireland in the tournament thus far and must win for Scotland to avoid a seventh successive defeat for the first time since 1998.
Scotland are seeking a first win in Rome since 2006.
Robinson said: "Nick was unfortunate to miss the game in Ireland through a hamstring problem and the challenge for him on Saturday will be to contribute as purposefully against the Italians as he did in his last game, against France."
Cuthbert, who won his solitary cap in the World Cup warm-up Test against Ireland last August, takes the place of Edinburgh's Matt Scott, who was thrust on to the bench following the injury to De Luca and made his debut after Jones was taken off.
Robinson said: "Jack has featured regularly for Bath this season. He's strong and we know from his involvement with the squad back in the summer how much it means to him to play for Scotland."
The pack is unchanged, with Geoff Cross retained at tighthead prop ahead of Euan Murray in an all-Edinburgh front row alongside captain and hooker Ross Ford and loosehead Allan Jacobsen.
Murray is named on the bench alongside replacement hooker Scott Lawson.
Richie Gray, Scotland's try-scorer in Dublin, is to combine again with Jim Hamilton in the second row, with Alastair Kellock again on the bench.
The back-row is comprised of John Barclay, Ross Rennie and David Denton, with replacement cover coming from Richie Vernon.
Scrum-half Mike Blair and fly-half Greig Laidlaw are to combine at half-back, with Chris Cusiter and Ruaridh Jackson in reserve.
Graeme Morrison is inside De Luca in the midfield, Evans is joined by Sean Lamont and full-back Stuart Hogg in the back three.