The Premier League champions will hope to take a step towards wrapping up a fourth title in just five years when they face David Moyes’s side.
However, City’s Achilles’ heel in the pursuit of top spot could prove to be their injury crisis at the back, with John Stones, Ruben Dias and Kyle Walker definitely out.
In addition, Aymeric Laporte and Fernandinho had to be replaced in the 5-1 win over Wolverhampton Wanderers on Wednesday and are now major doubts for the clash at the London Stadium.
Guardiola could head to the capital with just three fit, senior defenders in Joao Cancelo, Nathan Ake and Oleksandr Zinchenko, meaning a midfielder or youth player may have to deputise at the back.
However, in the more advanced areas, the City manager won’t have to contend with the same issues as all of his attack-minded players are fit.
The Sky Blues also don’t have a mid-week fixture, a rare luxury for Guardiola, so there might be less of an emphasis on rotation against the Hammers.
Here’s how we think he’ll line up at the weekend…