The Reds were finalists last year and will look to go one step further this time and lift Europe's most treasured trophy in Istanbul as they did in 2005.
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Last year, Liverpool won all six of their group games, but no English side has ever managed to win seven in a row, so they could make history.
But Napoli are a strong side and sit top of Serie A after picking up 11 points from their opening five games.
The Italian giants also have a good record against English sides in the Champions League and won against the Reds at the Diego Armando Maradona Stadium in 2018 and 2019.
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Therefore, this won't be an easy game for Liverpool, but if they do win, it will set them up perfectly for the rest of the group stage.
Napoli v Liverpool: Date and talkSPORT coverage
This Champions League Group A tie will take place on Wednesday, September 7.
Kick-off at the Diego Armando Maradona Stadium is scheduled for 8pm UK time.
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To tune in to talkSPORT or talkSPORT 2 through the website, click HERE for the live stream. You can also listen via the talkSPORT app, on DAB digital radio, through your smart speaker and on 1089 or 1053 AM.
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Napoli v Liverpool: Team news
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Napoli boss Luciano Spalletti is likely to be without Hirving Lozano after he was stretchered from the field against Lazio due to a nasty clash of heads.
Luckily, he hasn't suffered any facial damage but will likely miss this one.
The hosts will also be without Diego Demme as he recovers from a foot injury.
Meanwhile, Liverpool's midfield injury woes appeared to worsen against Everton as Fabio Carvalho had to be withdrawn at half time due to a dead leg.
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Jordan Henderson, Naby Keita, Alex Oxlade-Chamberlain, Calvin Ramsay and Ibrahima Konate all remain out.
Thiago Alcantara is expected back in training this week, but this match might come too soon for him.
Diogo Jota made his return from injury off the bench on Saturday, so Klopp could start the Portuguese forward.
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Napoli v Liverpool: What has been said?
Gabriel Agbonlahor on Liverpool's struggles: "Liverpool, for me, are not fighting for the Premier League title this season.
"They are fighting to stay in the top four because Arsenal are on it. Spurs are on it. They know how to win games. They have that winning mentality.
"There is something missing in that side.
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"Today [against Everton] is the sort of game where you would rely on Mane to come up with some sort of brilliance and make a goal. Mane's runs would open up more space for Salah.
"Salah doesn't look like he's going to score and that is not like Mo Salah. He has to come out wide and find space.
"The midfield didn't work. They played Fabinho as a sitter and in front of him Elliott and Carvalho. It just didn't work for me today.
"At the back, Robertson was dropped, Trent got taken off after 60 minutes. Something isn't right with that defence with Liverpool and they are dropping too many points."
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Napoli v Liverpool: Match facts
Napoli and Liverpool will meet in the UEFA Champions League group stage for a third time in the last five seasons. The Italian club won their home game against the Reds in both 2018-19 (1-0) and 2019-20 (2-0).
Napoli have won five of their six UEFA Champions League home games against clubs from England's Premier League, losing the other 2-4 to Manchester City in November 2017. Both of their last two such matches have been wins over Liverpool (October 2018, September 2019).
Liverpool have won each of their last three away games against Italian sides in European competition; they had only won three of their first 14 such visits beforehand (D3 L8).
This will be Napoli's seventh UEFA Champions League season, and first since 2019-20. The Azzurri have lost just one of their last 12 group stage games in the competitions (W5 D6), although that was to Liverpool in December 2018 (0-1).
Liverpool won all six of their group stages games in last season's UEFA Champions League. No English club have ever won seven consecutive group games in the competition's history.
Liverpool won all six of their away games in last season's UEFA Champions League, scoring 2+ goals each time. In the competition's history, only two sides have had longer away winning runs: Ajax (seven in March 1997) and FC Bayern München (seven in February 2014).
Napoli have only lost their first match of a UEFA Champions League season in one of their six previous campaigns in the competition (W3 D2), a 1-2 defeat to Shakhtar Donetsk in 2017-18.
Liverpool have only lost their opening match of a UEFA Champions League season in one of their last 12 appearances in the competition (W8 D3) - that defeat was, however, away at Napoli in 2019-20 (0-2).
Napoli will be Luciano Spalletti's fourth club managed in the UEFA Champions League, after Roma, Zenit St Petersburg and Internazionale. He will be the fifth manager to take charge of at least three different Italian sides in the competition, after Carlo Ancelotti (Parma, Juventus, Milan, Napoli), Alberto Zaccheroni (Milan, Lazio, Internazionale), Fabio Capello (Milan, Roma, Juventus) and Claudio Ranieri (Juventus, Roma, Internazionale).
Mo Salah scored seven goals in last season's UEFA Champions League group stage for Liverpool; only Ruud van Nistelrooy for Manchester United in 2004-05 (eight) has ever scored more in a single group for an English club in the competition. Salah also has 11 Champions League assists for the Reds, just one shy of the club's all-time record (12 by Steven Gerrard and James Milner).