A 79-year-old man with a 3-month history of weight loss and fever was diagnosed with disseminated histoplasmosis. When the infection became refractory to itraconazole therapy, posaconazole was prescribed. The patient became asymptomatic within 1 month of beginning treatment, and his general health improved. Posaconazole was discontinued after 6 months, and the patient has remained well since.