A 30-year-old man with advanced human immunodeficiency virus–infection presented with worsening dysphagia and odynophagia of 4 months’ duration. He had been on a revised combination antiretroviral regimen for 3 months with a recent CD4 count of 57 cells/mm3 and human immunodeficiency virus viral load of less than 50 copies/mL. Esophagogastroduodenoscopy showed erosive esophagitis and esophageal ulcers. Histopathologic examination was negative for herpes viruses and cytomegalovirus but showed intracellular yeast consistent with histoplasmosis. Histoplasma antigenuria was more than 39 ng/mL, which confirmed the diagnosis of disseminated histoplasmosis. After 3 weeks of treatment with liposomal amphotericin B and significant improvement, antifungal therapy was changed to itraconazole suspension. Histoplasma capsulatum is well known to cause gastrointestinal involvement in patients with acquired immunodeficiency syndrome, but esophageal involvement is rare.