Manchester United's hopes of salvaging their season in the Europa League suffered a stinging setback when they lost 2-1 at Danish side Midtjylland in the first leg of their last-32 clash on Thursday.
It should have been as straightforward an evening for United as it was for Borussia Dortmund and holders Sevilla who were among the high-profile clubs to secure comfortable wins as the Europa League's knockout stages got underway.
There was rare joy for former United stalwart Gary Neville when his Valencia side crushed Rapid Vienna 6-0. Tottenham Hotspur drew 1-1 at Fiorentina while Liverpool were held 0-0 at Augsburg.
United conceded the winner in the 77th minute when substitute Paul Onuachu pinched the ball on the edge of the area and swivelled before firing home a low bouncing drive.
One of the Old Trafford club's biggest close-season acquisitions Memphis Depay put them ahead in the 37th minute.
Midtjylland replied a minute before halftime when Pione Sisto pounced on a mistake from United captain Michael Carrick and scored with a low shot.
Sevilla's grip on the trophy showed no sign of loosening as their bid for a third straight triumph began with a 3-0 victory at home to Norway's Molde.
Fernando Llorente netted twice for the holders who, like United, were playing their first game in this season's competition having dropped into it after failing to reach the knockout rounds of the Champions League.
Sevilla opened the scoring against Molde when Llorente fired a pinpoint effort into the net off the post 10 minutes before halftime. The Spain striker doubled his tally when he held off his marker and blasted the ball into the roof of the net four minutes after the restart. Kevin Gameiro made it 3-0 with 18 minutes to go.
Lukasz Piszczek and Marco Reus were on target for Dortmund who recorded a 2-0 win at home to Porto on a night when the fixture list had an alluring look.
Meanwhile, Olympique Marseille suffered disappointment as they were beaten 1-0 at home by Athletic Bilbao while Bayer Leverkusen notched an impressive 1-0 win at Portuguese giants Sporting.
Valencia coach Neville has endured plenty of misery since taking over in December but, having claimed his first La Liga victory at the weekend and, on his 41st birthday, his side ran riot against Rapid Vienna as Santi Mina scored twice and set up three others.
St Etienne beat Basel 3-2, Anderlecht downed Olympiakos Piraeus 1-0, Galatasaray and Lazio drew 1-1 while Shakhtar Donetsk and Schalke 04 shared a goalless draw.