Manchester United were dumped out of the League Cup after losing on penalties to second-tier Middlesbrough who reached the quarter-finals having withstood a late onslaught to secure a 0-0 draw in extra time.
Middlesbrough were clinical in the shootout as hosts United faltered with England internationals Wayne Rooney, Michael Carrick and Ashley Young all failing to convert from the spot at Old Trafford.
It was a much better night for two of United's fiercest rivals, new coach Juergen Klopp tasting victory for the first time as Liverpool beat Bournemouth 1-0 while Manchester City thrashed Crystal Palace 5-1.
There was more woe for managerless Aston Villa who lost 2-1 at Southampton. Maya Yoshida and Graziano Pelle put the hosts two goals up before Scott Sinclair netted a late consolation from the penalty spot.
United became the latest high-profile casualty in the fourth round after Tuesday night saw Arsenal knocked out by second-tier Sheffield Wednesday and Chelsea beaten by Stoke City.
"It's very disappointing," coach Louis van Gaal told reporters. "We have to solve this problem, we have to finish our chances.
"I'm pleased with some performances of my players but I am also disappointed with some of my players. That's the life of a manager."
Manchester United 0-0 Middlesbrough (Middlesbrough win 3-1 on penalties)
Liverpool 1-0 Bournemouth
Manchester City 5-1 Crystal Palace
Southampton 2-1 Aston Villa