Whole inactivated virus (WIV) vaccines derived from the FLA cell line protect cats against challenge with feline immunodeficiency virus (FIV). To discover whether the protective effects of WIV could be reproduced by the isolated Env component, either WIV or immunoaffinity-purified FIV gp120 from the FL4 cell line was administered to cats. Although both vaccines induced high levels of virus neutralizing antibodies, purified Env was much less effective than WIV in protecting cats against viraemia. However, reduced virus load in PBMCs was evident in all Env-immunized cats compared to controls. Analyses of antibody responses to bacterial expression products of FIV Env, which were high in Env-immunized cats but low in animals receiving the WIV vaccine, suggested that the partially denatured, monomeric Env induces a less effective antiviral immune response than WIV. Hence, the superior immunogenicity of WIV may be due to the presentation of the native oligomeric structure of Env on virions.