The story picks up slightly over a year after the original game and follows several AMS agents investigating a zombie outbreak in Italy.

The protagonists are tasked with finding the source of the attack while also locating a fellow missing agent, known as G. The House of the Dead 2 is a rail shooter light gun game.

This is expanded upon with more paths than the original which also lead a greater variety of stage layouts and locations, although the general story itself will always remain the same.

During the chaos, James and Gary face Judgment, consisting of the impish Zeal and his giant, headless, axe-wielding armored puppet, Kuarl.

Upon meeting, the group faces the Hierophant, an amphibious monster which heads an assault on Venice's waterways and Central Plaza.

It is revealed that Caleb Goldman, a wealthy businessman who financed Dr. Curien's creations leading to the 1998 incident, is now responsible for the new wave of zombies attacking the city.

The two quickly race to the Colosseum, only to discover Amy and a wounded Harry, injured by the Strength, a massive, chainsaw-wielding zombie, which James and Gary manage to kill.

With his plans ruined and unable to escape, Goldman commits suicide by throwing himself off the roof of his building, though he warns the players that "in time, a successor will come".

Players are given different endings based on the following conditions: In the good ending, James and Gary run into Thomas Rogan, the other main character from the first game, who tells them that G and Harry are all right, and that they should head off to their next battle "as long as they have the will to live" (in the case of James) or "as long as there is an answer" (in the case of Gary).

In the normal ending, as James and Gary leave the building, they are greeted by G, Amy and Harry, as well as a large group of civilians, who thank them for their help.

The staff praised it for its expansion of its predecessor's gore and intensity, but noted that the lack of a light gun accessory for the Dreamcast version was slightly disappointing.