Lazio opt for Antonio Candreva, Keita Balde and Brayan Perea in their must-win trip to Ludogorets.
It kicks off at 18.00 GMT and the Biancocelesti lost the first leg 1-0 at home, meaning they have to win in Bulgaria or crash out of the Europa League at the Round of 32.
Miroslav Klose is on the bench to begin with, as Coach Edy Reja hopes the youth of Keita and Perea can be more effective.
Federico Marchetti returns in goal after a month out with muscular and stomach problems.
Ludogorets: Stoyanov; Junior Caicara, Mantyla, Moti, Minev; Aleksandrov, Fabio Espinho, Zlatinski, Misidjan; Marcelinho; Bezjak
Ludogorets bench: Cvorovic, Choco, Terziev, Juninho Quixada, Dani Abalo, Lumu, Michel
Lazio: Marchetti; Konko, Biava, Ciani, Radu; Biglia, Ledesma, Onazi; Candreva, Perea, Keita
Lazio bench: Berisha, Lulic, Mauri, Gonzalez, Cana, Klose, Kakuta