Ketoconazole, amphotericin B, 5-fluorocytosine, and combinations of these drugs were compared as therapy for chronic cryptococcal meningitis in steroid-treated rabbits. Two hours after treatment of rabbits with meningitis with single drugs the mean cerebrospinal fluid concentration of 5-fluorocytosine was 4.4 microgram/ml, that of amphotericin B was less than 0.3 microgram/ml, and that of ketoconazole ranged from less than 0.2 to 0.8 microgram/ml. Serial quantitative cultures indicated that amphotericin B was the best single-drug regimen. Ketoconazole provided little or no additive effect when used in combination with fluorocytosine or therapeutic doses of amphotericin for two weeks. However, the combination of ketoconazole plus amphotericin B was at least as effective as amphotericin B plus 5-fluorocytosine over a two-week treatment regimen. The addition of ketoconazole to subtherapeutic dose of amphotericin B significantly increased the killing of cryptococci in cerebrospinal fluid.