Fluconazole, a new oral triazole antifungal agent, was tested against Blastomyces dermatitidis in vitro and in a murine model (pulmonary challenge) and compared with ketoconazole, an oral imidazole known to be effective against this agent in mice and in humans. Although fluconazole appeared less active than ketoconazole in vitro, in experiments involving 3 weeks of treatment and 2 months of observation, fluconazole was greater than 10 times as potent (mg/kg) in vivo against blastomycosis (prolongation of life). In the model neither drug was curative at the doses and regimens used. A possible explanation for the efficacy of fluconazole in vivo is its favorable pharmacokinetic profile (i.e., prolonged serum concentrations that exceeded the MIC for the pathogen after oral administration). Dosages of 100 mg/(kg.d) were tolerated for 3 weeks without evident toxicity.