In an 11-year period, 74 cases of North American blastomycosis were recognized. During the first five years of the study hydroxystilbamidine isethionate was used as the drug of choice and was successful in 21 of 23 trials. Subsequently a series of treatment failures occurred and lead to more frequent use of amphotericin B although the use of hydroxystilbamidine isethionate was continued. Over the entire 11-year period 53 patients were treated with hydroxystilbamidine isethionate initially, and 31 were considered to have been treated successfully with this agent. One case of hepatic toxicity occurred, 5 patients died while receiving hydroxystilbamidine isethionate, and 9 patients were treated successfully with amphotericin B. Amphotericin B was the drug used initially in 12 patients. In 10 the outcome was successful, in one severe toxic reactions lead to the successful use of hydroxystilbamidine isethionate, and in the remaining patient neither drug was successful. The marked renal toxicity of amphotericin B greatly limits its usefulness, and in cases of slowly progressive North American blastomycosis, hydroxystilbamidine isethionate continues to be a useful therapeutic agent.