The game follows the fictional events of February 26, 2000, fourteen months after the 1998 Curien Mansion incident in The House of the Dead. AMS agent G has gone missing and his last known location is Venice, Italy. The city of Venice becomes chaotic when a strange zombie breakout takes place. American AMS agents James Taylor and Gary Stewart are dispatched, along with Amy Crystal and Harry Harris, to investigate and evacuate the populace. They suddenly encounter the impish Zeal, who had recently dealt with G. Upon finding G alive but wounded, James and Gary converse with him and G gives them a field journal showing the bosses and weak points. The pair are then met with a massive undead horde, similar to the kind from the Curien Mansion incident. They continue on, trying to save the town's civilians from the zombies.