Endocardial involvement associated with disseminated histoplasmosis has been infrequently documented, especially among patients with prosthetic valves. The therapeutic approach to these patients is also not yet clearly defined. A 54-year-old man with prosthetic valve endocarditis due to histoplasmosis was successfully treated with amphotericin B. A review of the literature suggests that the optimal form of therapy is likely a combination of surgical replacement of the involved valve and high dose amphotericin B. Successful therapy with amphotericin B alone may, however, be achieved if surgery is not a viable option.