Manchester United suffered a 2-1 defeat to PSV Eindhoven and lost Luke Shaw to a double leg fracture on their return to Champions League action.
In what was United's first match in the competition proper since April 2014, play was stopped for almost 10 minutes as Shaw received treatment following Hector Moreno's heavy tackle.
The England full-back was taken from the field on a stretcher in the 25th minute but it did not seem to hamper the visitors and they took the lead through former PSV star Memphis Depay's 41st minute strike.
However, their lead did not last long as Moreno levelled the scores during the lengthy period of stoppage time at the end of the first half.
After the break, United dominated possession but they found themselves behind after Maxime Lestienne's early cross found Luciano Narsingh at the far post in the 56th minute and he made no mistake, sealing all three points for the Dutch side.
After his heroics on debut against Liverpool, Anthony Martial was handed his first United start and he got an early chance to stretch his legs, running at the heart of the PSV defence before misplacing an attempted pass to Memphis.
The pair combined again in the seventh minute with Memphis firing a low cross to Martial at the near post, however the Frenchman could not get enough power on his shot to trouble Jeroen Zoet.
United's early dominance was stalled when Shaw, making his Champions League debut, burst into the PSV penalty area on a trademark run before going down under a challenge from Moreno, who got both the ball and the man.
Play was then suspended for almost 10 minutes as Shaw, who was caught by Moreno's trailing leg, received treatment for a double fracture of the leg before being stretchered off the field to a standing ovation from the Philips Stadion.
The injury seemed to dampen the atmosphere inside the stadium and both sets of players took a while to get going after seeing Shaw - who will be a huge miss for both United and England - leave the field.
Marcos Rojo came on in place of Shaw and went straight into the heart of United's defence with Daley Blind switching to left-back and they were tested straight away as Joshua Brenet slipped Narsingh in behind the United defence, but he could not time his run and was adjudged offside.
PSV were growing in confidence but it was the Dutch club's former favourite Memphis who broke the deadlock in the 41st minute, skipping past the challenges of Santiago Arias and Jeffrey Bruma before firing a low shot past Zoet.
Minutes later, the Netherlands international could have made it two but flashed a shot wide of the far post before Zoet produced a smart save to deny Chris Smalling.
All eyes were on the fourth official and there were eight minutes of added time after the earlier delay. It took PSV just two to grab an equaliser through Moreno, who rose highest to head the ball past David de Gea via a deflection from the head of Blind.
After the break, it was United who started the more confident of the two sides as Martial combined with Memphis, but the latter's shot did not have enough power to trouble Zoet.
Louis van Gaal's side were dominating possession but they could not make it count as PSV took the lead in the 57th minute as Narsingh headed home Lestienne's brilliant cross.
United could have been on level terms just five minutes later when Juan Mata spurned a glorious chance after being played in on goal by Bastian Schweinsteiger's pass.
The Spain international's touch let him down at the vital time and it was the story of the Premier League side's night as they continued to dominate the ball but there was no way through a well-marshalled PSV defence, led by former Chelsea player Bruma.
With just 15 minutes left, Van Gaal threw on Marouane Fellaini in place of Ander Herrera but their luck did not change as Mata failed to hit the target from distance and Martial skewed a shot wide of the far post.
United continued to push forward, which allowed PSV to break on the counter-attack and they should have wrapped up all three points through former Newcastle striker Luuk de Jong, but he fired his effort over the bar from close range.
However, it did not come back to haunt the home side as they held on for a famous victory, leaving United in third in Group B after Wolfsburg's win over CSKA Moscow.
The Bundesliga side are United's next opponents on September 30 for what could prove a crucial fixture as Champions League football returns to Old Trafford.