Diego Simeone's Atletico will hope to bury memories of last season's 3-1 quarter-final defeat by Real at the Bernabeu.
They will fancy their chances as they handed Real their only loss in all competitions so far this season by 3-1 when Carlo Ancelotti's side visited the Metropolitano in late September.
Since then LaLiga leaders Real have won 15 of 19 games in all competitions, dropping points in the league on only three occasions, while Atletico have struggled with inconsistent results and sit in fifth spot, 10 points off the pace.
Real are top on 48 points, level with this season's surprise package Girona, who have been drawn at home to fellow LaLiga side Rayo Vallecano in the last 16.
Barcelona, who are third in LaLiga seven points behind the leaders, will travel to play fourth division Unionistas.
Last-16 draw
Unionistas vs Barcelona
Tenerife vs Mallorca
Getafe vs Sevilla
Osasuna vs Real Sociedad
Valencia vs Celta Vigo
Athletic Bilbao vs Alaves
Atletico Madrid vs Real Madrid
Girona vs Rayo Vallecano
