Any joy United fans felt after Liverpool, last season's runner-up, lost its opening match evaporated on Wednesday when the defending champion was beaten 1-0 at newly promoted Burnley.
And with injuries having decimated his defence, which last season was the joint best in the league, manager Alex Ferguson has problems to overcome if his team is not to drop more points at Wigan on Saturday.
Liverpool has already bounced back into form after its opening loss to surprise leader Tottenham and is at Aston Villa on Monday, while potent-looking Arsenal hosts out-of-form Portsmouth and Chelsea is at Fulham.
United was without central defenders Rio Ferdinand and Nemanja Vidic and goalkeeper Edwin Van der Sar at Burnley and may again have to cope with a depleted back line - which is where Ferguson sees most of his team's problems.
"Burnley had a good 10-minute spell which won it for them," Ferguson said. "They caused us a lot of problems with their balls in behind our back four, turning us towards our own goal.
"(The goal) was a very good strike, a marvelous hit, but we didn't defend it well. The player should have been covered but one or two of our midfield players were running out when the ball was played across."
But United was also laboured in attack and seems to be struggling to get to grips with the change in lineup and formation necessitated by the offseason sale of Cristiano Ronaldo to Real Madrid for a world record 80 million pounds ($135 million).
Michael Carrick had a penalty saved and spurned a scoring chance, while Michael Owen - who scored freely in preseason after his free transfer from Newcastle - scuffed an opportunity and was replaced after 63 minutes.
Ferguson said his team won't miss as many chances at Wigan, which beat West Ham 2-0 in its opener but then lost 1-0 at home to newly promoted Wolverhampton Wanderers.
"Hopefully we get as many (chances) on Saturday," Ferguson said. "Michael Carrick had what I thought was the best chance when the ball was squared to him in the box but he decided to take a touch on the ball and lost the opportunity. Michael Owen missed a great chance in the first half, Ryan Giggs had one in the second half and Wayne Rooney had a couple of chances.
"Our players are all disappointed, it was a bad result for us," Ferguson said. "But I'm sure we'll get a response."
Burnley manager Owen Coyle is now preparing his team for Sunday's visit from Everton, which was mauled 6-1 by visiting Arsenal last weekend, but expects United and Ferguson to recover quickly and challenge for a record fourth straight title.
"He is the best manager in world football and I still expect Manchester United to be champions," Coyle said.
Arsenal did not play a midweek Premier League because it was at Celtic in Champions League qualifying and should rack up another victory against a Portsmouth team shorn of its best players and on a run of two 1-0 losses.
While Pompey has sold players including Peter Crouch and Glen Johnson to help pay off debt and is a strong candidate for relegation, Arsenal is enjoying a strong start with new arrival Thomas Vermaelen dominant in central defence.
"Thomas has been a good signing for us, he's a very good player, a very good defender," goalkeeper Manuel Almunia said. "He has a good left foot, he is good in the air and is very competitive. Now he has to keep it going."
Also Saturday, Birmingham hosts Stoke, Hull hosts Bolton, Manchester City hosts Wolves and Sunderland hosts Blackburn.
Tottenham's 5-1 win at Hull on Wednesday followed a shock 2-1 victory over Liverpool and means the north London club has won its opening two matches for just the second time in 14 years. It goes for a third straight win at West Ham in Sunday's third game.
While Tottenham will be without goalkeeper Heurelho Gomes because of a torn thigh muscle, the team has few worries in attack with Jermain Defoe set to continue up front after his first hat trick since December 2004 took his tally to seven goals in 11 games since returning to Spurs in January.
"His form is absolutely electric," Tottenham manager Harry Redknapp said. "He looks stronger than I have ever seen him and I have known him since he was 14. He has done a lot of work in the gym in the summer and he looks even more explosive."
Middlesbrough, Newcastle and West Bromwich Albion, the three teams relegated from the Premier League last season, are among six teams tied on seven points at the top of the second-tier League Championship.
Boro hosts Doncaster on Saturday, with Newcastle at Crystal Palace and West Brom hosting Ipswich.
