Three hundred twelve patients with antimony-resistant kala-azar were randomized into three groups. The first group (A) received pentamidine isethionate intravenously three times each week until parasitological cure was achieved. Group B received pentamidine concomitantly with a 20-day regimen of sodium stibogluconate. Group C received pentamidine injections that were followed by 20 days of sodium stibogluconate therapy. All patients became afebrile after 10 injections of pentamidine. Parasitologic cure was achieved in approximately 98% of the patients who had 33 or more injections of this drug. The addition of the antimony compound did not appear to enhance the rate of parasitologic cure. Three patients continued to have parasites after 40 injections of pentamidine. After six months, the rate of parasitologic cure was significantly higher in Group C (pentamidine followed by sodium stibogluconate) than in either Group A or B. Forty patients relapsed after apparent parasitologic cure and were successfully treated with five additional injections of pentamidine, followed by a course of antimony therapy. Minor side effects with pentamidine included an uneasy feeling during intravenous injection (12%), intestinal disturbances (6%), cellulitis (5%), abscess formation (1%), and allergic manifestations (2%). Major reactions to this drug included hyperglycemia (10%; reversible in 6% and irreversible in 4%), and delayed hypoglycemia (8%). Four deaths were associated with the administration of this compound. It is concluded that pentamidine is an effective but toxic drug for the treatment of antimony-resistant kala-azar. When used, treatment schedules should be continued for some time after disappearance of amastigotes from bone marrow or spleen aspirates, rather than adhering to a fixed number of injections. Better results were achieved by pentamidine followed by a course of antimony, but no advantage was achieved by the simultaneous administration of the two drugs.