The new triazole derivative SCH 56592 has been tested in a National Committee for Clinical Laboratory Standards-adapted in vitro susceptibility test, and its activity against 12 isolates of Blastomyces dermatitidis yeast-like forms has been compared with those of amphotericin B, itraconazole, and fluconazole. SCH 56592 was the most active of the four compounds, with an MIC at which 90% of the isolates are inhibited of 0.06 microgram/ml and a minimal fungicidal concentration at which 90% of the isolates are inhibited of 4 micrograms/ml. The results of the treatment of mice infected with B. dermatitidis with three different doses of SCH 56592 (25, 5, or 1 mg/kg of body weight), amphotericin B (1 mg/kg), or itraconazole (150 mg/kg) confirmed the potent activity of SCH 56592. Survival was prolonged at each dose of SCH 56592, and sterilization of the lungs occurred in the high-dose group but not in the groups treated with itraconazole or fluconazole. SCH 56592 is a promising new azole antifungal drug that should be studied in humans with blastomycosis.