Specific pathogen-free cats were experimentally infected with feline immunodeficiency virus (FIV) and subsequently exposed to common infectious pathogens and immune stimuli over a 3-year period. Cats with preexisting FIV infection showed signs of disease after exposure toHaemobartonella felis, Toxoplasma gondii, feline herpesvirus-1, and feline calicivirus similar to signs in non-FIV-infected cats, although they were more severe. No adverse effects of immunization with inactivated rabies virus vaccine and a synthetic polypro-line immunogen were observed in either FIV-infected or non-FIV-infected cats, whereas the application of a diphtheria-tetanus-pertussis vaccine caused transient fever and lymphadenopathy in both groups of animals. Primary immune responses to pathogens or immunogens were usually delayed or diminished in FIV-infected compared with non-FIV-infected cats. Repeated infections and immune activation had no significant effects on the levels of FIV-specific antibodies or on the proportion of peripheral blood mononuclear cells (PBMCs) containing FIV proviral DNA. However, FIV-infected cats that were not exposed to immune stimuli had lower CD4+T-lymphocyte numbers and lower CD4+/CD8+T lymphocyte ratios at the end of the 3-year study than FIV-infected cats exposed to cofactors. The latter also had normal levels of interleukin-2 receptor (IL-2R) and major histocompatibility class II (MHC-II) antigen expression on PBMCs, while FIV-infected cats not exposed to cofactors had up-regulated IL-2R and down-regulated MHC-II antigen expression. It was concluded that repeated immune stimulation did not have a deleterious effect on the course of FIV-induced immunodeficiency.