We studied the penetration of two imidazoles (ketoconazole and vibunazole) and two triazoles (itraconazole and UK-49,858) into cerebrospinal fluid (CSF) of rabbits with and without meningitis. There were wide differences in degree of penetration of these drugs into CSF, from less than 3% to 66% of simultaneous serum concentrations. UK-49,858, which has little protein-binding, penetrated freely while itraconazole, which is highly protein-bound, could not be detected in CSF. Intermediate concentrations of vibunazole and ketoconazole were found in CSF. Presence of meningeal inflammation modestly increased CSF concentrations of ketoconazole but had no significant effect on penetration of the other three drugs. The excellent penetration of UK-49,858 indicates that it has promise for treatment of CNS fungal infections.