Two friends, one with AIDS, developed severe pulmonary blastomycosis but differed markedly in clinical course. The human immunodeficiency virus-negative patient responded completely to ketoconazole; the patient with AIDS died of progressive disseminated infection despite treatment with fluconazole and amphotericin B. Epidemiologic investigation suggested a common source of infection, but serologic evaluation and environmental cultures were unrevealing. EcoRI digestion of the Blastomyces dermatitidis isolates showed identical restriction fragment patterns that differed from patterns obtained from other clinical isolates. Analysis using a Histoplasma capsulatum ribosomal DNA probe that cross-hybridizes with B. dermatitidis showed that the isolates from the two patients were identical and different from others. Thus, the patients were probably infected with the same strain, possibly from a common source. These data indicate the critical role of cellular immunity in patients with blastomycosis, show that there are multiple genotypes of B. dermatitidis, and suggest that DNA restriction analysis is a useful epidemiologic tool.