Nude (nu/nu) mice were infected with Histoplasma capsulatum and treated with varying doses of 3 drug regimens: oral ambruticin, i.p. amphotericin B, and amphotericin B plus oral rifampin. Therapy with amphotericin B alone was the most effective regimen. High-dose ambruticin (50 mg/kg of body wt every 8 h) led to significantly prolonged survival compared to that of untreated control animals, but not to long-term cures. Addition of rifampin produced no benefit and might actually have decreased the efficacy of amphotericin B; this combination may be deleterious in a setting of immunodeficiency.