Both sides were unbeaten in the group stage but it is Ludogorets who, surprisingly, had the better record by winning five and drawing one of their group games.
Ludogorets are also doing far better domestically this season. They are top of Bulgaria's 'A Group' top division while Lazio are down in 10th in Serie A.
Slovenia's Roman Bezjak was Ludogorets's top scorer in the group stage and should be fit to start on the eve of his 25th birthday.
Whoever wins this two-legged tie will go on to play either Dynamo Kiev or Valencia in the last 16.
Possible starting lineups
Lazio: Marchetti, Ciani, Cavanda, Novaretti, Lulic, Anderson, Onazi, Ledesma, Cana, Balde, Perea
Ludogorets: Stoyanov, Barthe, Moti, Caicara, Choco, Zlatinski, Marcelinho, Espinho, Quixada, Bezjak, Misidjan
Sports Mole says: 2-0