Later that year, Polidori used his employer’s unfinished work as the basis of a novella: Lord Ruthven, who bears an intentional resemblance to the notorious Lord Byron, is a jaded, charismatic nobleman who must feed upon the blood of the living in order to continue his unnatural existence. Polidori’s creation became the prototype for most subsequent literary vampires, ranging from Count Dracula to Lestat. When “The Vampyre”  appeared in The New Monthly Magazine on 1 April 1819, it carried the by-line “A Tale by Lord Byron.” Polidori was outraged and Byron tried, unsuccessfully, to disassociate himself from it.

He published The Fragment at the end of his poem Mazeppa that same year, to try to convince people he did not wrote the whole story. Unfortunately for both of them the novel was an immediate and phenomenal success, so popular that it was included in the first and third editions of Byron's collective works. It was popular, because everyone knew perfectly well that Lord Ruthven was a portrait of Byron. Five more editions were published in London, and it was translated into French and Italian. There is little doubt that the success of Polidori’s story was due to the fact that most people believed it had been written by his employer; even Goethe considered it Byron’s best work. The confusion was serious, and Polidori ended up receiving thirty pounds for a work, in its own way, as influential and long-lasting as his master's own, even if it appears he partly stole it. In fact, there were two originals, and a couple of spoofs.

The first adaptation of “The Vampyre” appeared in 1820 with Cyprien Bérard’s novel, Lord Ruthwen ou les Vampires, described as 'le Don Juan vampirique'. This novel was rumoured to have been written by Charles Nodier, who eventually wrote his own version, the influential drama Le Vampire, a play that initiated the first “vampire craze.” By June of 1820, three vampire plays were running simultaneously in Paris theatres. In the same year, James Robinson Planché’s The Vampire; or, The Bride of the Isles, an adaptation of Nodier’s play with a Scottish setting, appeared on the London stage. Another adaption was produced by no less than Alexandre Dumas in 1853; this is bypassing the actual opera version, created by Heinrich Marschener and librettist Wilhelm Wolbrucke in 1828. Other versions of Polidori’s story were popular for years to come.

Polidori published another novel in 1819, entitled Ernestus Berchtold, which also involves supernatural elements. His journal indicates that it was a version or summary, perhaps as Frankenstein by Mary's record first existed, of this novel that was his contribution to the evening.