Premier League champions Manchester City face German side RB Leipzig, while Tottenham play Italian giants AC Milan.
Chelsea also have German opposition in Borussia Dortmund.
Elsewhere, French champions Paris St-Germain have drawn Bayern Munich.
The last-16 first legs will take place on 14-15 and 21-22 February, with the second legs on 7-8 and 14-15 March.
Full last-16 draw:
RB Leipzig v Manchester City
Club Bruges v Benfica
Liverpool v Real Madrid
AC Milan v Tottenham
Frankfurt v Napoli
Borussia Dortmund v Chelsea
Inter Milan v Porto
Paris St-Germain v Bayern Munich
BBC Sports