The meeting of last term's top two is the highlight of the weekend Premier League programme, in which Arsenal and Manchester United face tricky away games while Chelsea will expect to record a second straight win over a promoted side.
Liverpool will make the short motorway trip east to Manchester knowing they should be arriving as title holders.
With three matches to play last season, Brendan Rodgers' side were nine points clear of City, who had two games in hand but had just lost 3-2 at Anfield.
Liverpool then lost at home to Chelsea, and then frittered away a three-goal lead at Crystal Palace, allowing City to finish top by winning their four remaining games.
The Manchester side were the more impressive of the two on the opening weekend of the new campaign, easing to a 2-0 win at Newcastle United with goals by David Silva and Sergio Aguero.
Liverpool, now without last season's leading scorer Luis Suarez, were below their best at home to Southampton and needed a late goal from Daniel Sturridge to win 2-1.
City's neighbours Manchester United visit Sunderland on Sunday hoping to shrug off last weekend's surprise 2-1 home defeat by Swansea City in their first league match under new manager Louis van Gaal.
The experienced Dutchman will have spent the week trying to restore his players' confidence, which he was said was "smashed" by the Swansea result.
"We make steps and you have to learn from your steps," he told the club's in-house television station MUTV.
The late kickoff (1630 GMT) on Saturday sees Arsenal travel to Everton, needing to recover physically from a long trip to Istanbul in the Champions League playoff round on Tuesday, when they were somewhat fortunate to draw 0-0 with Besiktas.
Last April. Arsene Wenger's team lost 3-0 at Everton, one of several emphatic away defeats which they need to improve on this season.
Chelsea, comfortable 3-1 winners at Burnley on Monday, when Spain's Diego Costa scored on his competitive debut, play last season's Championship winners Leicester City, who were impressive in holding Everton 2-2 in their first Premier League match for 10 years.
The other two matches in London are both derbies with special managerial interest.
Harry Redknapp, sacked by Tottenham Hotspur two years ago despite leading them to fourth place, returns to White Hart Lane in charge of Queens Park Rangers, with former Spurs midfield hero and manager Glenn Hoddle now in his coaching team.
Crystal Palace and West Ham United, both beaten by London rivals on the opening day, meet at Selhurst Park with the home club looking for a new boss.
Last season Palace won both meetings on their way to finishing unexpectedly high in 11th place, having been widely tipped for relegation.
But they have to regroup quickly after Tony Pulis, the architect of that achievement, left two days before the start of the new season, reportedly following a dispute about new transfer targets.