Specific pathogen-free cats were infected with the Maryland strain of FIV (FIV-MD) for the purpose of assessing the effects of FIV infection on the central nervous system (CNS). Two separate studies were performed, involving a total of 13 infected cats and six age-matched, sham-inoculated controls. All animals infected with FIV-MD seroconverted by 8 weeks post-infection and virus was recovered from peripheral blood mononuclear cells of all infected cats. All of the infected animals had lower absolute CD4+ cells counts and decreased CD4+/CD8+ ratios. Virus was recovered from the cerebrospinal fluid (CSF) of certain infected individuals, and antiviral antibody and pleocytosis were evident in the CSF of the majority of infected cats. Additionally, virus was recovered from tissue explants from the cerebellum, midbrain and brainstem of one sacrificed FIV+ cat. Specific neurological changes included anisocoria, delayed righting reflex and delayed pupillary reflex, as well as delayed visual and auditory evoked potentials, and marked alterations in sleep patterns similar to those reported for human immunodeficiency virus (HIV)-positive individuals. Histological evaluation revealed the presence of perivascular cuffing and glial nodules in FIV-infected cats. These results indicate that FIV causes an acute neurological disease that closely resembles the early neurological effects of HIV infection in humans and should serve well as an animal model for lentivirus-induced CNS disease.