Jonny Gray will win his first cap in nearly two years and Dave Cherry his first since the Rugby World Cup when Scotland face Italy in their Six Nations opener on Saturday.
Gray, 30, has not featured for Gregor Townsend's side since the win over the Azzurri in the 2023 championship. He suffered a serious knee injury in May that year which kept the lock out for more than a year.
But he has been in good form for Bordeaux and with Scott Cummings injured, earns a recall to start alongside Grant Gilchrist in the second row.
Cherry, meanwhile, has been given the nod over Edinburgh team-mate Ewan Ashman to start at hooker.
It caps a remarkable turnaround in fortunes for the 34-year-old, who won his last cap at the World Cup before a concussion suffered after falling down a set of stairs on a team day off ruled him out of the tournament.
When naming the veteran hooker in his squad earlier this month, Townsend insisted his absence since was not a disciplinary issue.
In the absence of Sione Tuipulotu, Townsend has also turned to Stafford McDowall to fill the number 12 jersey. The Glasgow man will line up alongside his club colleague Huw Jones.
Duhan van der Merwe is also fit to start on the left wing after concerns over a calf injury. He lines up alongside Darcy Graham and Blair Kinghorn in a potent back three.
Jack Dempsey, who has only played 68 minutes since November's defeat to South Africa, has been left on the bench, with Townsend opting to stick with the back-row trio that started Scotland's last outing, the Autumn Nations Series success over Australia.
That means Jamie Ritchie wears six, with Rory Darge - who will co-captain the side alongside Finn Russell - on the openside flank and Matt Fagerson at number eight.
The teams
Scotland: Blair Kinghorn, Darcy Graham, Huw Jones, Stafford McDowall, Duhan van der Merwe, Finn Russell (co-captain), Ben White; Pierre Schoeman, Dave Cherry, Zander Fagerson, Jonny Gray, Grant Gilchrist, Jamie Ritchie, Rory Darge (co-captain), Matt Fagerson
Replacements: Ewan Ashman, Rory Sutherland, Will Hurd, Gregor Brown, Jack Dempsey, George Horne, Tom Jordan, Kyle Rowe
Italy: Tommaso Allan, Ange Capuozzo, Juan Ignacio Brex, Tommaso Menoncello, Monty Ioane, Paolo Garbisi, Martin Page-Relo, Danilo Fischetti, Giacomo Nicotera, Simone Ferrari, Dino Lamb, Federico Ruzza, Sebastian Negri, Michele Lamaro (captain), Lorenzo Cannone
Replacements: Gianmarco Lucchesi, Luca Rizzoli, Marco Riccioni, Niccolo Cannone, Manuel Zuliani, Ross Vintcent, Alessandro Garbisi, Simone Gesi
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