Late goals from Dries Mertens and Fernando Llorente earned Napoli a 2-0 victory as Liverpool made a slow start to their Champions League defence.
For the second season in a row, Jurgen Klopp's side were beaten in the group stage in Naples - they lost 1-0 last October - and it was more sloppy defending which saw the Group E game slip away from them in the final minutes.
The Reds had defended stoutly against some sustained pressure from the home side, but were unlucky to be punished when Jose Callejon skipped inside of Andy Robertson before making the most of minimal contact with the Liverpool defender and, when a VAR review failed to give the visitors a reprieve, Dries Mertens took full advantage to beat Adrian from the spot.
"For me it's clear and obvious, no penalty, because Callejon jumps before he has any contact," an unhappy Jurgen Klopp complained after the game.
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As Liverpool pushed for a late equaliser, Fernando Llorente doubled the lead during added-on time after a rare Virgil van Dijk mistake, profiting when the defender's mis-hit pass ran into his path and he slotted the ball home to spark wild celebrations on the home bench.
Victory was sealed - and the reigning champions of Europe had been beaten in the first game of their defence for the first time since AC Milan in 1994.
Liverpool defence gets off to a whimper
Liverpool were hoping for better than their limp showing at the Stadio San Paolo last season, but found themselves caught out on the break early on when, as they would have feared, Lorenzo Insigne found space in behind Trent Alexander-Arnold. But from his pull-back Fabian twice pulled simple saves out of Adrian from a good position.
Liverpool responded when Jordan Henderson's lob found Sadio Mane unmarked on the edge of the box, but his heavy touch took him wide of Alex Meret's post and, from a tight angle, it was simple enough for the goalkeeper to turn his effort round the post with his legs.
Napoli: Meret (7), Di Lorenzo (6), Koulibaly (8), Manolas (6), Mario Rui (7), Callejo (6), Fabian (7), Allan (7), Insigne (6), Lozano (6), Mertens (7).
Subs: Zielinski (6), Llorente (7), Elmas (6).
Liverpool: Adrian (7), Alexander-Arnold (7), Matip (6), Van Dijk (5), Roberton (6), Milner (6), Henderson (6), Fabinho (7), Salah (5), Firmino (6), Mane (5).
Subs: Wijnaldum (5), Shaqiri (n/a)
Man of the match: Kalidou Koulibaly
There was little more to shout about from either side before the break although it took a last-gasp challenge from Alexander-Arnold to take the ball off Insigne's foot as he prepared to shoot.
The second half did not take so long to liven up. It was less than four minutes old when Liverpool were indebted to a world-class save from Adrian to stay level, with the goalkeeper somehow tipping over Mertens' far-post header when he looked certain to score.
When the visitors did get chances to attack, their front three looked out of sorts; it was summed up when Mane hung onto the ball too long as Liverpool broke before over-hitting a simple pass across to the unmarked Mo Salah.
Liverpool were left to rue those misfiring attacks when Callejon took a late tumble under pressure from Robertson, the referee pointed straight to the spot and Mertens found the bottom corner, despite a commendable effort from Adrian.
It was already looking like a case of deja vu for Liverpool at this point, but things got worse in added time when Van Dijk's uncharacteristic error set up Llorente, who had been in the defeated Spurs squad in last season's final, to slot under Adrian and seal three points for the hosts.
'Not a typical Liverpool performance'
Former Liverpool defender Phil Babb told The Debate:
"It was comfortable, they created chances, I think they had four on target which was an improvement from last season when they only had one. But it wasn't a typical Liverpool performance; we didn't see Andy Robertson or Trent Alexander-Arnold bombing forward.
"Sadio Mane looked sharp, Mo Salah looked sharp at times, they did create chances but it was a masterclass from Kalidou Koulibaly - he was like the Virgil van Dijk of last season, and Liverpool got no joy out of him. It was a couple of sucker-punches.
"After that Adrian save, you thought 'yeah, coming out of this 0-0, it's a good point', but unfortunately they lost it."
- Napoli have now won five of their six Champions League home games against English opposition (L1 - a 2-4 defat to Man City in November 2017).
- Liverpool have lost their opening Champions League match of a new campaign for only the second time (P12 W6 D4 L2), and for the first time since a 0-2 defeat to Valencia in September 2002.
- Liverpool have lost six of their last eight away games in the Champions League (W2), as many as in their previous 25 such matches in the competition.
- Napoli striker Fernando Llorente has now scored a Champions League goal for four different clubs (Juventus, Sevilla, Spurs and Napoli) - the joint-most sides of all Spaniards alongside Fernando Morientes.
Chelsea host league leaders Liverpool on Renault Super Sunday - live at 4pm on Sky Sports Premier League; Kick-off 4.30pm.
The Reds' next Champions League game is at home to Red Bull Salzburg, who thrashed Genk 6-2 in their opening game, on October 2.