There are few clinical data concerning the use of fluconazole, a triazole antifungal agent with in vitro activity against Blastomyces dermatitidis, in the treatment of human blastomycosis. We conducted a multicenter, randomized, open-label pilot trial comparing two daily doses of fluconazole (200 mg and 400 mg) in the treatment of non-life-threatening, non-CNS blastomycosis. Twenty-four patients were enrolled in the study, and 23 patients were evaluable for efficacy analysis. Overall, treatment of 15 (65%) of 23 patients was successful, including eight (62%) of 13 who received 200 mg daily and seven (70%) of 10 who received 400 mg daily. The mean duration of therapy for successfully treated patients was 6.7 months. Of the six patients whose prior antifungal therapy had failed, all six eventually responded to fluconazole treatment. We conclude that fluconazole (200 mg to 400 mg daily) given for at least 6 months is moderately effective treatment for blastomycosis.