This paper describes the salient features of a new model for chronic cryptococcal meningitis in cortisone-treated rabbits. Normal rabbits soon recovered after intracisternal inoculation of Cryptococcus neoformans, but cortisone-treated animals developed chronic progressive meningitis that was fatal in 2-12 weeks. Incidence and severity of infection was related to cortisone dose, not to inoculum size. The number of mononuclear cells that migrated into the subarachnoid spaces and cerebrospinal fluid of infected rabbits was strikingly reduced by cortisone treatment. Rabbits with cryptococcal meningitis were febrile; their high body temperature did not confer resistance to this infection. Cortisone-treated rabbits provide a new and expedient laboratory model for cryptococcal disease. Potential applications include study of the pathogenesis of cryptococcosis, investigation of the immunobiology of the CNS in chronic meningitis, and in vivo evaluation of newer anticryptococcal treatment regimens.