Gian Piero Gasperini's side will have mixed memories of facing Spanish opposition at this stage of the competition.
Last season, they made history by beating Valencia in the round of 16 to reach their first-ever Champions League quarterfinal.
This year, the Italian side once again got past the group stages, finishing second in Group D behind Liverpool. On the final day of group stage action, they managed to beat Ajax to pip the Dutch side and move into the knockout rounds.
Atalanta are in good form coming into this game, having won each of their last three games. On Sunday, they beat Napoli 4-2 as they build up a head of steam going into the business end of the season.
Halfway through those group stages, it didn't seem like Real Madrid would qualify from Group B. They had lost to Shakhtar Donetsk at home, and drawn against Borussia Monchengladbach.
However, they eventually made it through as group winners after beating Gladbach in the final group game.
Real are going through a bit of an injury crisis at the moment, but have still kept themselves afloat in the La Liga title race.
Even though they have played a game more than their city rivals, Real currently find themselves just three points behind Atletico Madrid at the moment.
Atalanta vs Real Madrid Head-to-Head
This game will be the first time that Atalanta and Real Madrid face each other in a competitive clash.
Atalanta form guide: W-W-W-D-D
Real Madrid form guide: W-W-W-W-L
Atalanta vs Real Madrid Team News
Hans Hateboer is injured, and will be Atalanta's only confirmed absentee ahead of this game. However, both Cristian Romero and Berat Djimsiti are walking a tightrope, and will miss the second leg in Madrid if they are booked in this game.
Injured: Hans Hateboer
Real Madrid's injury crisis has shown no signs of easing up. In fact, it's only gotten worse, with Karim Benzema confirmed as an absentee for this game.
The likes of Sergio Ramos, Marcelo, Eden Hazard and Eder Militao remain out of contention.
Injured: Sergio Ramos, Karim Benzema, Marcelo, Alvaro Odriozola, Eden Hazard, Rodrygo, Federico Valverde, Dani Carvajal, Eder Militao
Atalanta vs Real Madrid Predicted XIs
Atalanta Predicted XI (3-4-1-2): Pierluigi Gollini; Rafael Toloi, Cristian Romero, Berat Djimsiti; Joakim Maehle, Maarten de Roon, Remo Freuler, Robin Gosens; Josip Ilicic; Luis Muriel, Duvan Zapata
Real Madrid Predicted XI (4-3-3): Thibaut Courtois; Lucas Vazquez, Raphael Varane, Nacho Fernandez, Ferland Mendy; Casemiro, Toni Kroos, Luka Modric; Marco Asensio, Vinicius Junior, Mariano Diaz
Atalanta vs Real Madrid Prediction
Real Madrid could face a tough time in this game against Atalanta. This is largely thanks to the ridiculous number of injuries that they are grappling with at the moment.
We expect Atalanta to pull of a surprise victory in Italy this week.
Prediction: Atalanta 2-1 Real Madrid