BALB/c mice infected intraperitoneally with Coccidioides immitis were treated with cyclosporin (CyA) subcutaneously. CyA prevented infection when treatment was started at day zero. When treatment was delayed until day 6 after infection, the mice that received either 75 or 25 mg/kg per day survived, but those treated with 7.5 mg/kg per day had the same mortality rate as controls. The higher doses of CyA prevented dissemination of the fungus from the peritoneum to the lung but did not eliminate the peritoneal infection. In vitro, CyA inhibited the growth of the mycelial phase of eight test strains of C. immitis at a concentration of 1.0 microgram/ml. One or two strains of 10 other fungi were tested for susceptibility to CyA; only Aspergillus niger was inhibited, at a concentration of 0.1 microgram/ml. CyA is structurally unrelated to the polyenes and imidazoles and has a very restricted spectrum of antifungal activity. CyA may represent a new class of antifungal agents with a novel mechanism of antifungal activity.