In an effort to induce a strong immune response that might protect against feline immunodeficiency virus (FIV) challenge infection, three groups of five specified pathogen-free (spf) cats each were immunized subcutaneously with different FIV antigen preparations. Immunizations were done at weeks 0, 2, and 4 with 100 microg of recombinant SU from an FIV Zurich 2 (FIV Z2) strain expressed by E. coli (group 1) or the baculovirus expression system (groups 2 and 3) adsorbed on aluminum hydroxyde and administered with QS-21 (groups 1 and 2) or Freund's adjuvant together with the recombinant nucleocapsid protein (protein NC) of rabies virus (group 3). Protein NC was described to act as an exogenous superantigen. Group 3 cats demonstrated the highest detectable antibody response to the vaccine antigen as determined by ELISA and Western blot analysis. All immunized cats together with seven control animals were challenged with 20 CID50 of cat lymphocyte-grown FIV Z2 3 weeks following the last immunization. Whereas virus was readily recovered from peripheral blood lymphocytes of seven of seven nonvaccinated control cats following this challenge dose, virus was not recovered from two cats of groups 1 and 2. All cats in groups 2 and 3 showed a provirus load significantly decreased to 3% of that of controls up to week 8 after challenge infection. Eleven of 15 vaccinated cats and 5 of 7 control cats developed virus-neutralizing antibodies by week 8 after challenge infection. The two cats negative on virus isolation remained seronegative, developed no detectable virus-neutralizing activities, but were repeatedly positive in provirus PCR. Moreover, starting at week 1 after challenge, both cats showed the lowest provirus load in their respective groups. These results indicate that immunization with recombinant FIV SU in conjunction with appropriate adjuvants may lead to partial protection against FIV challenge infection.