They have failed to win on any of their last 15 visits, even despite their rapid rise since their last win on L4. In fact, the Reds have won this fixture for the last four seasons - the first time they have done so since 1981 - and will hope for a fifth successive home win over City.
But this City team is as ideally equipped to end their winless run against the Merseyside outfit. All but confirmed as league champions already, Pep Guardiola's have failed to win just two of their first 22 top-flight matches this season and have not lost in domestic competition since April 23.
However, all of City's last six defeats under Guardiola have come away from home - including their only loss in any competition this season as a weakened side lost at Shakhtar Donetsk in their final Champions League group stage game.
Of their many wins this term, City thrashed Liverpool 5-0 in September, their biggest margin of victory over the Reds since 1937, although the two teams were largely even before Sadio Mané's 37th-minute red card.
Jürgen Klopp's fourth-placed side have lost just two of 26 matches in the league, cup competitions and in Europe since then, but despite such improvement are an astounding 18 points adrift of the leaders.
But that statistic on its own ignores that they are just one of a myriad of clubs left trailing in City's wake this term, Guardiola's charges a frankly ridiculous 15 clear of second-placed Manchester United.
Yet Guardiola and co. will know that Liverpool are well capable of puffing out their chests and achieving what would be a huge statement with three points.
But that should not detract from the good feeling around the club. They have not lost in 17 games in all competitions since a defeat at Tottenham Hotspur back in October.
And the Merseyside outfit are unbeaten in 18 home games since last April - last losing on the same date that City were last beaten by a team in English competition.
Question marks have arisen over their ability in the big games, having failed to recreate the kind of form that saw them top the table for clashes against fellow 'big six' teams last season.
Their only league win against the teams around them came at home to Arsenal in August, losing to City and Spurs and drawing at Anfield against United and Chelsea and also throwing away a commanding lead to draw 3-3 away at the Gunners most recently.
And there would be no better way for them to quash such doubts over their big-game ability than to overcome the best team in England, and possibly in Europe, and deny them the chance of an unbeaten league season and also a league double over Liverpool.
Van Dijk - the most expensive defender in the world - is expected to make his Premier League debut for Liverpool despite a reported knock in training while top goalscorer Mohamed Salah has been passed fit to play.
The Egyptian, having missed the Reds' win over their Merseyside rivals after being absent for the New Year's Day win at Burnley, is back from a groin strain and will hope to be among the goals again with 17 in 21 league games.
City will return to a full-strength eleven after naming a mix-and-match side to face Bristol City in the League Cup earlier this week, though captain Vincent Kompany is unavailable.
The Belgian defender is sidelined by the latest occurrence of a troublesome calf injury which forced him off after only 11 minutes of the win at Newcastle United on December 27.
Gabriel Jesus is improving from a knee injury having avoided ligament damage and could be back within a fortnight, but is out for the trip to Anfield.
Benjamin Mendy (ACL) is a long-term absentee while youngster Phil Foden (ankle) is also missing.
Raheem Sterling, with 18 goals to his name this term, will look to score against his former club for the first time since a £50 million switch to City in the summer of 2015.
Recent form (all competitions)
Manchester City: WDWWW
Liverpool 2-1 Everton (FA Cup third-round)
Manchester City 2-1 Bristol City (League Cup semi-final first-leg)
Manchester City have gone 16 games in all competitions without a win at Anfield.
City have not done a league double over Liverpool since way back in 1936-37 - they won their first ever top-flight title that term.
Liverpool have kept nine clean sheets in their last 13 league games at Anfield, though Leicester City are the only team to score in a league game on L4 and not earn a point.
The Merseyside club have not won four Premier League games in a row since December 2016 - the fourth game of that run a home win against City.
Liverpool have not lost a Premier League game on home soil since a 2-1 defeat to Crystal Palace in April 23, going 15 games unbeaten since then. (W7, D6)
The Reds could go their first 12 home games without defeat in the Premier League for the first season since 2011-12.
City's 5-0 thrashing of Liverpool earlier this season was Reds boss Jürgen Klopp's joint-heaviest defeat as a manager, level with his Mainz side's 6-1 loss to Werder Bremen in October 2006.
No opposing manager has beaten Pep Guardiola more often than Klopp in all competitions (four, level with current United and former Real Madrid and Inter Milan boss José Mourinho).
Sergio Agüero has scored in all of his six matches against Liverpool at the Etihad Stadium but has not scored in any of his seven career appearances at Anfield. (Five with City, two with Atletico Madrid)
City would become the first team since Wimbledon in 1986-87 and only the second team since World War Two to beat all Chelsea, Liverpool and Manchester United in a single season top-flight campaign.
City's current 30-game unbeaten run is the fifth-best in top-flight history: Liverpool - 31 (1987-88), Leeds United - 34 (1968-69), Chelsea - 40 (2004-05), Nottingham Forest - 42 (1977-78), Arsenal - 49 (2003-04).
Andre Marriner is the man in the middle for his 16th Premier League game of the season, his third involving Liverpool.
The 47-year-old was the match official for the Reds' 4-1 defeat at Spurs and also their 4-0 win over Bournemouth on the South Coast, while he has been the referee for one City game - a 1-0 win at Newcastle three weeks ago.
Birmingham FA official Marriner has dished out 36 yellow cards and two straight red cards in the top flight this term. His career highlight was the 2013 FA Cup final, in which City were famously beaten by Wigan Athletic at Wembley Stadium.