The English Premier League giants have a two-goal lead to take to Belgium after a 3-1 win at Old Trafford last Tuesday, while Lazio have a slender 1-0 advantage for their second leg against Bayer Leverkusen in Germany.
A 2-0 win for Brugge at the Jan Breydelstadion would be enough to take them through at United's expense (on the away goals rule), but United -- three-time winners of the Champions League -- are confident after Marouane Fellaini's late third goal in the first leg.
Brugge boss Michel Preud'homme, on the other hand, was less optimistic after conceding the third goal in Manchester.
"This last goal was very bad for the confidence," said former Belgian international Preud'homme.
"It's a pity we let this one in," added the 56-year-old, who guided Brugge to the Belgian Cup last season.
Manchester United -- winners in 1968, 1999 and 2008 -- didn't feature in the competition last season but had previously reached the group stages for 18 years in succession.
Lazio go to Bayer Leverkusen hoping to defend a one-goal advantage and reach the main draw for the first time since the 2007/08 season.
Keita Balde Diao's second-half winner at the Stadio Olimpico in Rome was the difference between the two sides last week, but Leverkusen are seasoned campaigners who have made the round of 16 in three of the last four seasons and were only edged out on penalties by 2014 runners-up Atletico Madrid at that stage last campaign.
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