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Blood Blockade Battlefront centers around the crime fighting organization "Libra" and their battles in Hellsalem's Lot, formerly known as New York City. Hellsalem's Lot was created when a portal to the "Beyond" opened, becoming a paranormal melting pot of monsters, magic and the everyday mundane life, and it is up to Libra to clear the streets of trouble and prevent the horrors of this city from spreading to the outside world.

In 2012, the world allegedly comes to an end at the hands of a "human-made" virus, ravaging the global populace and leaving only children under the age of thirteen untouched. It is at this time that vampires emerge from the recesses of the earth, likely followed by age-old horrors of the dark thought only to be myth.