Strongyloides stercoralis is an intestinal nematode that can cause disseminated infection in an immunocompromised host. It is most commonly acquired in developing countries. It was previously a common infection in many parts of the United States, particularly in the Appalachian region, but is rarely identified currently. Here, we describe a patient born and raised in Appalachia, with no history of travel outside the United States, who presented with chronic lymphocytic leukemia and S. stercoralis hyperinfection characterized by acute respiratory failure, altered mental status, and extended-spectrum-beta-lactamase Klebsiella pneumoniae bacteremia. Despite prompt identification of the parasite on sputum microscopy and initiation of therapy with oral ivermectin and meropenem, the patient subsequently died. This case highlights the continued possibility of S. stercoralis infection in patients from Appalachia.