After the events in Raccoon City, an underground anti-Umbrella organization forms to put an end to Umbrella. Leon S. Kennedy is sent to investigate the ocean liner STARLIGHT which is rumoured to be carrying a new Bio-Organic Weapon (B.O.W) developed by Umbrella, but eventually contact is lost with him.

The player takes the role of Barry Burton, who is sent to complete Leon's mission. When he arrives on board he discovers that an outbreak similar to the one in Raccoon City has occurred on the ship. Eventually Barry meets up with a girl named Lucia and finds Leon, and the trio must escape from both the ship and an Umbrella submarine before once again returning aboard the STARLIGHT for the final showdown with the B.O.W.