Cristiano Ronaldo's Covid-enforced absence was keenly felt as Juventus stumbled to a 2-0 defeat to Lionel Messi's Barcelona on Wednesday.
Messi, 33, set up Ousmane Dembele to put Barca in front after quarter of an hour in Turin, adding a second himself from the penalty spot in stoppage time.
Alvaro Morata had three goals ruled out for offside for Juve who played the final five minutes a man down after Merih Demiral was sent off for a second yellow card.
Barcelona are top of Group G with six points after two games with Juventus on three. The reverse fixture takes place at the Camp Nou on December 8.
"This was our best game all season," said Barcelona coach Ronald Koeman.
"This is a big win against an important European side and we were able to play the football we're trying to impose.
"I'm very happy with the game and the character displayed by the team, it is a great victory."
Portuguese star Ronaldo was left out by Juve for the match in Turi, two weeks after testing positive for coronavirus.
The 35-year-old, the top scorer in the history of the Champions League with 130 goals, needed to test negative 24 hours before the game.
A furious Ronaldo posted a photo on Instagram, with the comment: "Feeling good and healthy! Forza Juve! #finoallafine."
Ronaldo first tested positive for Covid-19 on October 13 while playing with Portugal, and has been in self-isolation since returning to Italy.
He has reportedly tested positive 18 times, according to Portuguese TV1.
It was a first defeat for new Juve head coach Andrea Pirlo, whose last game as a player for the Turin giants was a loss to Barcelona in the 2015 Champions League final.
"We knew it would be a difficult game, they are further along the path, they have players more experienced in these games, while we are under construction," said Pirlo.
"We need to grow. I hope to have the other players back soon.
"I have no other solutions, those who play have to stay 90 minutes, so it's difficult when there are matches close together."
The loss could have been heavier for Juve as under-pressure Koeman's side bounced back after a 3-1 defeat against Real Madrid at the weekend followed a 1-0 loss to Getafe.
Barcelona president Josep Maria Bartomeu also resigned on Tuesday along with his board of directors, following mounting pressure from fans and his public falling out with six-time Ballon d'Or winner Messi.
"After the defeat against Real Madrid it was important to get off to a good start," said defender Sergi Roberto.
"We're delighted, there are only two goals' difference but it could have been a lot more. We dominated, we created chances."
The breakthrough came when Messi pinged a sublime cross-field ball for Dembele who ran at two defenders before his long-range strike deflected off Federico Chiesa and looped in over Wojciech Szczesny in the Juventus goal.
Morata had the ball in the net just after but the goal was ruled offside after a VAR viewing.
The Spain striker, at Juve on a season-long loan from Atletico Madrid, latched on to a Juan Cuadrado cross to turn home after half an hour, but again he was ruled offside. A VAR review then denied him for a third time on 55 minutes.
Juventus saw Demiral dismissed in the closing minutes, and Messi sealed victory from the spot following a foul by Federico Bernardeschi on Ansu Fati for his 117th Champions League goal.