The Nerazzurri have given their new Uruguay international his maiden starting birth, playing in a midfield three, as Roma hand debut to Destro
The former Porto man will play alongside Freddy Guarin and Walter Gargano, who will support Wesley Sneijder in the No.10 role.
Elsewhere for the Nerazzurri, they are relatively unchanged from the side that beat Pescara last weekend. Antonio Cassano joins Diego Milito up front, whilst Luca Castellazzi retains his place in goal as Samir Handanovic remains injured.
For Roma, Zdenek Zeman makes three changes from the side that drew 2-2 with Catania last weekend. Miralem Pjanic and Michael Bradley lose their place in the starting XI to Alessandro Florenzi and Panagiotis Tachtsidis.
Up front, former Inter youth player Mattia Destro comes in for his first start, replacing Erik Lamela.
Otherwise, it is an unchanged Giallorossi team, as they look for their first three points under the Czech coach.
Inter (4-3-1-2): Castellazzi; Zanetti, Silvestre, Ranocchia, Nagatomo; Guarin, Gargano, Pereira; Sneijder; Cassano, Milito
Roma (4-3-3): Stekelenburg; Piris, Burdisso, Castan, Balzaretti; Florenzi, Tachtsidis, De Rossi; Destro, Osvaldo, Totti