The clash marks the second time in the space of 15 days that the two sides meet at the Etihad Stadium, with Chelsea coming out on top in the previous clash.
Full-back Branislav Ivanovic scored the winner on that occasion, as Manchester City's 20-match unbeaten run across all competitions came to an abrupt halt with Chelsea winning 1-0.
In one of many twists the FA Cup often seems to serve up, the top four in the Premier League were all drawn together in the fifth round, with Arsenal set to welcome Liverpool on Sunday.
And the knowledge that one of their biggest rivals will definitely exit the tournament is sure to focus the minds of both sets of players.
As well as holding home advantage, City head into the encounter fresher than their opponents after their Premier League clash with Sunderland was postponed on Wednesday due to adverse weather conditions.
However, the game denied City the opportunity to return to winning ways after Manuel Pellegrini's normally free-scoring outfit drew blanks in their last two fixtures - the loss to Chelsea, followed by a 0-0 draw at Norwich City.
City's top scorer Sergio Aguero (hamstring), midfielder Fernandinho (groin) and centre-back Matija Nastasic (knee) are all set to miss out.
Midfield pair Samir Nasri and Javi Garcia have recently returned to training following knee injuries, but their involvement looks doubtful.
Chelsea had been riding the crest of a wave as they followed their win at City with a 3-0 home triumph over Newcastle United.
Jose Mourinho's men suffered a slight setback on Tuesday, however, after they were held to 1-1 draw at West Brom, with Victor Anichebe cancelling out Ivanovic's opener.
The Stamford Bridge outfit remain at the top of the Premier League table, though City now have a game in hand and a far superior goal difference.
Chelsea have enjoyed a period of success in the world's oldest cup competition in recent times, lifting the trophy on four of the last seven occasions.
They last won the FA Cup in 2012, defeating Liverpool 2-1 at Wembley.
Captain John Terry could come back into contention for Mourinho following a muscular issue, while Gary Cahill is struggling with a calf problem.
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