This article argues that a number of the most prominent Gothic spaces in American Romanticism were influenced by a Renaissance conception of medicine. I show how Romantic writers in the United States retained key elements of a miasmal model of disease, applying them to narratives in which Gothic architectural space and cognitive interiority become radically blurred. In the first section, I provide a detailed genealogy of miasma, charting the moral universe of the ancients and the development of rational medicine so as to understand Marsilio Ficino’s conception of miasma as an invasive foreign agent that transmits itself through the scale of nature to jeopardize the spiritual coherence of the self. The second section applies this notion of miasma as a thematic literary context to the United States of the nineteenth century, briefly to Ralph Waldo Emerson and more assiduously to four representative texts: Edgar Allan Poe’s “The Masque of the Red Death” (1842), “The Fall of the House of Usher” (1839), “Ligeia” (1838), and Nathaniel Hawthorne’s The House of the Seven Gables (1851). I conclude with the modernist afterlife of this miasmal paradigm in William Faulkner’s Gothic masterpiece, Absalom, Absalom! (1936). In this, I examine the cultural power that an idealist way of thinking about human health continued to possess well into modernity.