Objective:To evaluate the efficacy of immunopurified class I human histocompatibility leukocyte antigen (HLA) to protect against SIV infection.Methods:HLA class I antigens were immunopurified from a human B‐lymphoblastoid cell line. Groups of four macaques were vaccinated subcutaneously with four doses of the immunogen in adjuvant, or with adjuvant alone and subsequently challenged intravenously with 10 median monkey infectious doses of cell‐free SIVmac‐32H. Infection was determined by polymerase chain reaction for SIVmacproviral DNA and by virus isolation. Antigen‐specific humoral and cellular immune responses were monitored.Results:Macaques immunized with the HLA molecules produced anti‐HLA class I antibodies that inhibited SIV replicationin vitroand downregulated autologous T‐cell proliferation against irradiated C8166 cells. They were partially protected (two out of four) from virus infection for at least 33 weeks when challenged with SIV grown in human cells. All four control animals were infected.Conclusions:This demonstration of partial protection, together with our previous work reporting that vaccination with allogenic cynomolgus lymphocytes can protect against challenge infection with SIV grown in simian cells, suggests that allogenic immune response induced before or during establishment of HIV infection may have important implications for AIDS disease progression.