If you don't know the story, I'd be surprised. Briefly, it follows a wealthy prince named Prospero, who invites his friends and fellow royals into his "castellated abbey" to avoid the plague raging outside. As his townspeople die out, he believes he will be perfectly safe and even throws a masquerade party to celebrate his sagacity. The massive gala takes place throughout seven rooms, each decorated with a specific color theme. The only room that most guests avoid is the final room, a black chamber with a foreboding ebony clock. When a strange-looking guest appears, wearing the garb of a victim of the plague, Prospero confronts him and, well, no words sum it up better than the final words in the story: "And Darkness and Decay and the Red Death held illimitable dominion over all."
Despite being one of Poe's popular mainstream works, "The Masque of the Red Death" has invited substantial critical commentary too. Often, it is read as an allegory about the inevitability of death — a reading complicated by Poe's outspoken dislike of using allegory. Particularly inviting to scholars is the question of the disease. Some suggest it stands in for tuberculosis, a disease which Poe had personal experience with; his wife Virginia was suffering from it at the time the story was written. Poe also witnessed a cholera epidemic while in Baltimore and the "red death" may reference that disease. Bubonic plague, also known as the black death, is another candidate, especially because of the symbolism of the final black room.
If you ask me, the "Red Death" is the "Red Death" and nothing more. In creating a fictitious disease, Poe makes the story about all disease, not any specific one. But, it is because of this debate and these questions of "What did Poe mean?" which help the story be more than just a scary tale but one of depth and value. Overall, "The Masque of the Red Death" stands as one of Poe's most important — and most entertaining — prose works.
*The image at the top right is by Harry Clarke, published in 1919, with an added red tint. I couldn't resist.