Scanning and transmission electron microscopy was performed on the various phases ofCoccidioides immitis, exposed for different periods of time to the imidazole antifungals miconazole and ketoconazole.The development of spherules into endospores, which takes place in cultures under normal growth conditions, was suppressed in the drug treated cultures.Typical ultrastructural changes were localized at the cell periphery and in the vacuolar system. The drugs did induce changes in mature, resting endospore cultures and in cultures incubated statically at room temperature. Aerobically growing endospores were not susceptible to either drug. The transformation of arthroconidia into mycelium was fully prevented after treatment. Mycelial cells were most susceptible to the antifungals for necrosis was induced in a substantial part of the hyphae after exposure for 24 h.The imidazole drugs, miconazole and ketoconazole, interfere markedly with progressive murine coccidioidomycosis [13][14][15]17]. Treatment, after intranasal instillation of arthrocondia, limits the subsequent replication of the spheruleendospore phase of Coccidioides immitis in the lungs. Early ketoconazole treatment, in particular, markedly reduces dissemination 1-13, 15] characterized by fungal invasion of the peritoneal organs. These activities are associated with high rates of survival in appropriately treated animals. Corresponding findings in man [12,20,23] also indicate that the drugs are effective in local and in disseminated coccidioidomycosis. However, in animals, as in man, biocure rates are low and prolonged therapy is required.In animals it was apparent that exposure of endospores to plasma concentrations of ketoconazole of 10#gml-1 was therapeutically beneficial [15]. We sought therefore to determine in the present study if this concentration of ketoconazole or miconazole altered the structure of the different morphologic phases of C. immitis. Recent publications [21,22] have described the saprobic and parasitic forms of C. immitis in clear detail and have updated earlier morphologic studies [5, 6, 10, 19] on C. immitis.On the other hand, surface characteristics of C. immitis, as seen with scanning electron microscopy, have not been reported in detail. We have therefore limited our descriptions in this paper to developmental changes in fungal structure during normal growth and to alterations that occur after exposure of the organism to miconazole and ketoconazole.