Histoplasma capsulatum, a dimorphic fungus found world-wide, is endemic to regions of the Mississippi and Ohio River valleys and portions of Central and South America. Initial infection can present with acute pulmonary symptoms or remain clinically asymptomatic, with disease course generally guided by degree of inoculum and underlying immunosuppression. A chronic, progressive course of weight loss, oral ulceration, and fatigue has been associated with elderly males. We present a 79-year-old man with a chronic, progressive course of oral lesions, odynophagia, and weight loss who was found to have histoplasmosis on oral biopsy performed for suspicions of oropharyngeal squamous cell carcinoma. Histoplasma urine antigen, serum complement fixation antibody titers, and fungal tissues were all negative despite validated sensitivities in the >90% range. Our case report highlights the critical role of tissue biopsy in establishing a diagnosis of oropharyngeal histoplasmosis.