Manchester City fell to a second successive defeat - and a first Champions League group/league phase home loss in seven years - as Bayer Leverkusen claimed a 2-0 win at the Etihad.
Lyon were the last team to beat Man City at home before the knockout rounds in September 2018, winning 2-1. Pep Guardiola served a touchline ban that evening and was replaced in the dugout by Mikel Arteta.
But Guardiola had a front row seat for Tuesday's defeat. He made 10 changes to his starting XI from the weekend's Premier League loss at Newcastle, benching the likes of Erling Haaland, Phil Foden and Jeremy Doku.
But the fresh legs did not work, with Guardiola urging his side to pass the ball quicker from the early minutes of the game as Leverkusen outplayed their opponents.
It was a fast break that saw them score the opener too. Christian Kofane's superb cross was lashed home by Alejandro Grimaldo, despite Man City having dominated the early possession.
The hosts' best chance of the half came with the last kick as Tijjani Reijnders forced a fine save from former Brentford goalkeeper Mark Flekken. City finished the opening period with just two shots on target.
Guardiola bought on Foden, Doku and Nico O'Reilly at the break - but nine minutes later Leverkusen doubled their lead. Ibrahim Maza curled a wonderful ball into the box for Patrik Schick to nod home.
Haaland looked stone-faced on the touchline as the second went in, and it wasn't long before he was introduced alongside Rayan Cherki.
He almost had an immediate impact too, with a trio of chances falling his way. Two efforts went wide, while another - when he looked to be through - was smothered away from his feet by Flekken.
Man City did look brighter with their big guns, but it was not enough to beat a well-drilled Leverkusen, who are the first German team to win at the Eithad in the Champions League since Guardiola's Bayern Munich in October 2013.
The results will certainly give the Man City head coach plenty to ponder. None of the 10 players who came in had any real impact, while their reliance on Haaland being on the pitch and in form was glaring evident. The players were booed off the pitch by supporters at full-time too.
It could also be a bruising defeat for their overall Champions League hopes. Man City remain in the top eight for now, but that could change by the end of Wednesday's games. They will desperately want to avoid the play-off rounds, and will need to rediscover their form ahead of an away match at Real Madrid on Wednesday December 10.
Leverkusen will be boosted by a second successive Champions League win, both of which have come away from home. They move up to 13th place, two points behind Man City.
Man City boss Pep Guardiola to TNT Sports: "It was not the performance that we thought. I'll take full responsibility but I still think that the players that started are exceptional players but we missed something that we need in the highest level.
"They were very good. We also did good things, we had chances, but it was half chances, always with a block or something there.
"We didn't have that belief that 'ok, it's the moment to attack, to defend' and have the determination to make a movement and some situations that we can do. Sometimes it happens."
On whether 10 changes were too many: "If we win, it wouldn't have been a problem, so I accept that maybe it was a lot but if we're playing every two, three or four days... but maybe it was too much, seeing the result."
Bayer Leverkusen defender Jarell Quansah to TNT Sports: "It's an unbelievable feeling. Coming into tonight, we had a lot of senior players absent for a number of reasons, the boys managed to pull through. Everyone led tonight, it was a lot of character, fight and grit.
"They've got world class quality, a lot of their players tonight play for their countries. We defended a bit deeper than I would like to, but we got the win.
"I think we've got quality players. We're a completely new team, a lot of senior players from last year went and we had to step up this season. We have so much quality and youth, we want to implement how we want to play the game and we did that in parts.
"When we've got young players who have no fear. It's a massive occasion, some of the lads' biggest games tonight. Playing in the Champions League is a chance to prove yourself."
Bayer Leverkusen boss Kasper Hjulmand to TNT Sports: "What a performance. I'm very happy and proud of the boys. We played exactly what we wanted to do, we played with a lot of courage and were calm on the ball when we had to.
"We also need a little bit if luck and a good goalkeeper... there was a lot of courage and character in this team.
"It's so important when we have the ball that everyone needs to be involved. You can always make mistakes, but you should always look for the ball... no matter who you play, there's always space to play the ball.
"I'm very proud of this character of this young squad. We have a lot to learn but we did well today."
