Inter trail 1-0 to Bayern Munich, the side they defeated 2-0 in last season's final, ahead of the return leg at Munich's Allianz Arena on Tuesday, while United host Marseille after a 0-0 draw in the first leg.
Real are in a slightly stronger position ahead of the visit of Lyon on Wednesday, having procured an away goal in a 1-1 first-leg draw.
Of the heavyweight sides in action this week, however, it is only Chelsea who will approach their game with any sense of comfort as they lead FC Copenhagen 2-0 ahead of Wednesday's game at Stamford Bridge.
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In the unlikely event that the big guns require any further motivation, they need only look at the results of the four last-16 ties that have already been completed.
Italian league leaders AC Milan, chasing an eighth title, were stunned by Champions League debutants Tottenham Hotspur, while Shakhtar Donetsk upset Roma and Valencia went down to under-performing Bundesliga side Schalke.
Inter, the last Serie A representatives in European competition, succumbed to Bayern in the first leg through a 90th-minute goal by striker Mario Gomez, after Brazil goalkeeper Julio Cesar had spilled a shot from Arjen Robben.
United were held to a wretched goalless draw by French champions Marseille in the first leg but they remain top of the English Premier League and reached the FA Cup semi-finals with a 2-0 defeat of Arsenal on Saturday.
The 2008 champions are missing centre-back Rio Ferdinand and central midfielders Darren Fletcher and Michael Carrick through injury, while Marseille are without Brazilian striker Brandao, who is under investigation for rape.
"The first leg was a terrible game, a shocking match," said United coach Sir Alex Ferguson. "It will be a better game on Tuesday.
"Marseille will be planning on how they're going to score and I think they'll try to start the game very quickly - that's a certainty - and we have to be prepared for that."
Marseille, 2-0 victors at Rennes on Friday, are appearing in the knockout phase for the first time since they won the competition in 1993.
Real Madrid will hope Karim Benzema continues his goalscoring form as they tackle a Lyon team that eliminated them at the same stage of last season's competition.
The France striker netted Real's goal in the first leg against his former club and is enjoying his best run of form since his 35 million euros ($A48.27 million) switch from Lyon in 2009, having scored braces in his last three games.
Elimination for Real could herald a premature end to the tenure of Jose Mourinho, who is bidding to become the first coach to win the competition with three different teams following last year's success with Inter.
His former club, Chelsea, are not under quite the same pressure as they prepare to resume hostilities with Copenhagen.
A double from Nicolas Anelka earned the Blues a 2-0 victory in the first leg and the reigning English champions have had nine full days to prepare for the return fixture following their 3-1 win at Blackpool on March 7.
