Abstract Oral treatment of mice with R41 400, ketoconazole, after intranasal challenge with arthrospores of Coccidioides immitis prevented death at doses of 40 mg per kg of body weight per day. Doses of 160 mg per kg of body weight per day during 50 to 100 days eradicated the fungus from the lungs, liver, spleen, and kidneys of approximately one half of the infected animals. Resistance to the drug was not induced during prolonged treatment. Hydropic changes in the liver occurred in animals receiving doses of 160 mg per kg of body weight per day by the fiftieth day of treatment, but did not occur at lower doses.