Boss fights are a lot like House of the Dead III, in that they usually involve some sort of chase, and there is the return of the 'Cancel Bar', which are certain spots on a bosses' body that you must shoot repeatedly to stop the attack. In addition to the normal fire, the player also has grenades that he can throw, as well as branching paths to travel through. The common enemies also have two other attacks, a normal attack which deals one point of normal damage, and a push attack which will knock the player down for a few seconds, leaving him vulnerable. The guns in the arcade version have motion sensors in them which forces you to shake off enemies if they get too close and try to bite you. The standard gun for the game is a Mini UZI fully automatic submachine gun. They gather all of the weapons they can find, and fight their way to the sewers, and try to find out more about the 'Goldman Case'. A week later, James' PDA goes off, and he finds out that there are undead in the AMS office building. They are gathering information in the 5th basement floor of the AMS offices, when suddenly the floor collapses due to an earthquake, leaving the agents trapped.

AMS agent James Taylor is back, and he now has a new companion with him, Kate Green. The year is 2003, three years after the events of House of the Dead 2.

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