The plot of the story revolves around the extraordinary relationship between Roderick and his twin sister. When the spectral figure of Madeline first appears, we cannot determine whether she is an actual living person or some form of hallucinated effigy. Although Madeline's status as a full-fledged human being remains ambiguous even at the work's conclusion, what is apparent is that she shares some type of psychic affinity with her brother, one that transcends the normal relationship between siblings. Some critical readers of the tale maintain that the physical resemblance between Roderick and Madeline implies that they are the offspring of an incestuous relationship. Others have suggested that Roderick must kill his sister to avoid the evil of perpetuating the Usher line through an immoral act of incest. But the issue of incest aside, it is evident that Roderick and Madeline Usher are so closely bound to each other that they appear to be elements of a single psyche. Indeed, in one reading of the tale, Roderick and Madeline are two faculties of the same soul. This would accord with Poe's theory of the inherent division of human personality and the innate tendencies of its parts to seek reunion.

The narrator here is not unreliable in the same way that the murdering narrators of "The Black Cat" and "The Tell-Tale Heart" are. He readily admits that his account may be discolored by his mood of gloom, but we never doubt the veracity of what he tells us, including the resurrection of Madeline, Roderick's death, and the abrupt collapse of the House itself. There are, however, many open-ended questions that are not resolved by the story's end. Thus, for example, we do not know whether Madeline intended to kill Roderick in their final embrace or to unite with him. Poe makes no effort to fill in these blanks for us. His purpose is to create and sustain a single effect in the reader's mind, and, at the end, we are convinced that the author has more than achieved this end.