The disease called the Red Death is fictitious. Poe describes it as causing "sharp pains, and sudden dizziness, and then profuse bleeding at the pores" leading to death within half an hour.

The disease may have been inspired by tuberculosis (or consumption, as it was known then), since Poe's wife Virginia was suffering from the disease at the time the story was written. Like the character Prince Prospero, Poe tried to ignore the fatality of the disease.[11] Poe's mother Eliza, brother William, and foster mother Frances had also died of tuberculosis. Alternatively, the Red Death may refer to cholera; Poe would have witnessed an epidemic of cholera in Baltimore, Maryland in 1831.[12] Others have suggested the pandemic is actually Bubonic plague or the Black death, emphasized by the climax of the story featuring the "Red" Death in the "black" room.[13] One writer likens the description to that of a viral hemorrhagic fever or necrotizing fasciitis.[14] It has also been suggested that the Red Death is not a disease or sickness at all but a weakness (like "original sin") that is shared by all of humankind inherently.