In the series, the vampire population is made up of many different species. Most people do not know vampires exist. The series shows how vampires evolve and deal with conflict between the species throughout history. The series is mostly about a new American species of vampires. This group was born American West in the late 1800's. The first of this new species is an outlaw named Skinner Sweet. After becoming a vampire, Sweet leans that he is a new kind of vampire. He is stronger and faster than other species. Sunlight does not hurt him. He has new strengths. He also has different weaknesses. The series shows his movements through several decades of American history. It also follows the only vampire he is known to have created, Pearl Jones. Jones is a young woman who was trying to work as an actress in the 1920's silent film industry. She was attacked by a group of European vampires who were hiding in Hollywood. Sweet saved her by giving her his blood. This turned her into an American vampire like him. After this, tried to get revenge on the vampires who attacked her. The relationship between Jones and Sweet is an important part of the series.
The first five issues had two stories in each issue. One story was by Snyder and the other by Stephen King. Both stories were drawn by Rafael Albuquerque. As of the sixth issue, Scott Snyder became the only writer. In its second year of publication, a spin-off mini-series was created. It was titled American Vampire: Survival of the Fittest. This mini-series was drawn by Sean Murphy. It is about a vampire-hunting organization from the main series.
- Skinner Sweet - An outlaw who lived in the Wild West. He was turned into a vampire when the blood from Percy, a vampire banker, fell into his eye during a fight while he was escaping from being hanged. In 1936, Sweet moved to Las Vegas. In Las Vegas, he opened a brothel and called himself Jim Smoke.
- Pearl Jones - Wanted to be an actress in the 1920s. She was attacked by a group of vampires led by a vampire director named B.D. Bloch during one of his parties. The vampires though she was dead and put her body in a pit in the desert. She was saved by Sweet when he dropped his blood on her eye. This turned her into a vampire. She has moved to Arrowhead, California. She is using the surname of her husband, Henry Preston and hiding from the other vampires.
- Henry Preston - Pearl Jones' husband, he is a jazz singer who decided to help Pearl to get revenge against the vampires who attacked her.
- James "Jim" Book - A detective who worked for Pinkerton Agency. He hunted and arrested Skinner Sweet. Sweet turned him into a vampire because of this. He made a deal with Abilena before the vampirism took full control of him. He would have a child with her if she would kill him.
- Abilena Camino/Book - Daughter of Felix Camino, her mother died at birth. She is James Book's god-daughter but she says she loves him romantically when she grows up. After Book's death, she takes his surname. With her daughter Felicia, she hunts Skinner Sweet for an organization called The Vassals of the Morning Star.
- Felicia Book - Fathered by James Book and his god-daughter Abilena on the night he dies. She is a member of The Vassals of the Morning Star. It is an organization that hunts vampires. She seems to have special abilities because her father was a vampire. These abilities are not fully known.
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- McMillan, Graeme (November 10, 2009). "American Vampire's Snyder Introduces Our Secret Toothy Cousins". io9. http://io9.com/5401613/american-vampires-snyder-introduces-our-secret-toothy-cousins. Retrieved December 18, 2009.
- "American Vampire Trailer; King and Snyder Talk Scary, Not Sparkly, Vamps". Dread Central. http://www.dreadcentral.com/news/36416/american-vampire-trailer-king-and-snyder-talk-scary-not-sparkly-vamps.
- Vaneta Rogers. "Scott Snyder Prepares to Go it Alone on AMERICAN VAMPIRE". NEWSarama. http://www.newsarama.com/comics/scott-snyder-american-vampire-100728.html.
- Phegley, Kiel (October 26, 2009). "Scott Snyder & Stephen King Launch American Vampire". Comic Book Resources. http://comicbookresources.com/?page=article&id=23452. Retrieved December 18, 2009.
- Rogers, Vaneta (October 26, 2009). "STEPHEN KING Brings an American Vampire Tale to Vertigo". Newsarama. http://www.newsarama.com/comics/091026-american-vampire.html. Retrieved December 18, 2009.