Cats naturally infected with feline immunodeficiency virus (FIV) develop an AIDS-like syndrome whereas experimentally infected cats do not. To investigate the role of cofactors in the development of this disease in cats, 7 specific pathogen-free (SPF) and 12 random-source (RS) cats were infected with FIV. Over 4 years, infected cats developed similar phenotypic and functional immune abnormalities characterized by early and chronic inversion of CD4+:CD8+ cell ratios and significantly decreased mitogen responses compared with controls. Beginning 18–24 months after infection, 10 RS cats developed chronic clinical disease typical of feline AIDS, including stomatitis and recurrent upper respiratory disease; 4 SPF cats also developed chronic clinical disease, 2 with neurologic disease and 2 with B cell lymphomas. Thus, immunologic background is important in the type of disease that develops in cats infected with FIV, and FIV represents a promising animal model for studying the immunopathogenesis of AIDS in humans.