Just as with the original Left 4 Dead, Left 4 Dead 2 is a first-person shooter which pits players against hordes of zombie-like enemies. The game leads these 'Survivors' through the southeastern region of the US - from Savannah, Georgia through the bayou country, and climaxing in New Orleans’ French Quarter.

Players assume the role of four new 'Survivors,' each with their own personality and new dialog. Left 4 Dead 2 is set at roughly the same time as the original – just after the outbreak that turned most of the population into various zombie mutants.