The House of the Dead is a rail shooter light gun game. Players use a light gun (or mouse, in the PC version) to aim and shoot at approaching enemies. The characters' pistols use magazines, and are required to reload once each magazine is empty. A set of torches next to the magazine of each player represents remaining health. When a player is hurt or shoots a civilian, one of their torches is removed, signifying damage. A player is dead when all torches are lost. A player may then continue by inserting more credits, if playing on an arcade machine, and pressing the "continue" or "start" button. There are first-aid packs available throughout the game that will restore one torch. These are found either in the possession of civilians that the player has rescued or inside breakable objects. Similarly, there are also special items located in breakable objects that will grant a bonus to whoever shoots it.

Throughout the course of the game, players are given numerous situations in which their actions will have an effect on the direction of gameplay. For instance, in the beginning of the game, a civilian is about to be thrown off the bridge to his death. If players save the civilian, they will enter the house directly through the front door; however, if the civilian dies, players are redirected to an underground route through the sewers. This branching path system was also implemented in the sequels.

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