Disseminated histoplasmosis is an unusual infection in heart transplant recipients. We describe a 29-year-old man who developed fever, headache, and diarrhea 2 months after he received a heart transplant. Within days, diffuse pulmonary infiltrates, worsening hypoxia, and rising creatinine level supervened. Voriconazole was begun empirically, but the patient did not improve. A markedly elevated urine Histoplasma antigen test allowed a presumptive diagnosis of disseminated histoplasmosis, and treatment with liposomal amphotericin B was initiated. The patient became afebrile and felt better within a few days, and therapy was then changed to oral itraconazole solution. The diagnosis was confirmed with growth of Histoplasma capsulatum from bronchoalveolar lavage fluid. This is the third case of disseminated histoplasmosis reported in a heart transplant recipient and the first in which the urine Histoplasma antigen provided a valuable early clue to the diagnosis.