Javier Zanetti is on the bench for the first time in four years, as Inter launch Antonio Cassano and Diego Milito against Siena.
The captain had not been rested for a single Serie A game in the last four seasons, missing out only due to injury or suspension.
However, even 39-year-old Zanetti has to take a breather sometimes and is on the bench so Yuto Nagatomo and Alvaro Pereira can take the full-back roles.
Walter Gargano starts in midfield, while Wesley Sneijder supports Cassano and Milito, but the returning Cristian Chivu is on the bench.
Siena have only two points from three games so far this season, but are hoping to continue Inter’s San Siro taboo – not a single victory on home turf in all competition.
Alessandro Rosina is the support for Emanuele Calaio with Ze Eduardo taking a deeper role.
Inter: 1 Handanovic; 55 Nagatomo, 23 Ranocchia, 40 Juan Jesus, 31 Pereira; 19 Cambiasso, 21 Gargano, 14 Guarin; 10 Sneijder; 99 Cassano, 22 Milito
Inter bench: 12 Castellazzi, 27 Belec, 4 Zanetti, 6 Silvestre, 7 Coutinho, 11 Alvarez, 25 Samuel, 26 Chivu, 41 Duncan, 42 Jonathan, 44 Bianchetti, 88 Livaja
Siena: 25 Pegolo; 13 Neto, 24 Paci, 18 Felipe; 6 Angelo; 8 Vergassola, 10 D'Agostino, 57 Ze Eduardo, 3 Del Grosso; 27 Rosina, 11 Calaiò
Siena bench: 12 Farelli, 89 Marini, 7 Valiani, 9 Paolucci, 15 Dellafiore, 16 Verre, 21 Ribair, 33 Rubin, 34 Martinez, 77 Sestu, 81 Bogdani
Think you know your Italian football? Share your knowledge, tips and comments to win cash prizes in OLBG's tipster competition  - £5,000 monthly.