This report revisits the accidental discovery that protection against simian immunodeficiency virus (SIV) infection in the early successful experimental AIDS vaccine studies in Rhesus macaques was due to antibodies directed against human leukocyte antigens (HLAs). The inactivated virus vaccine approach was discarded because protection was due to the hosts immune reaction against the HLA acquired by SIV from the human cell lines in which it was grown, rather than against antigenic determinants of SIV itself. Subsequent studies have revealed that immune recognition of HLA on uninfected leukocytes also induces other factors that inhibit infection by both SIV and the human immunodeficiency virus. Pro and con aspects of immunization against HLA as a potential AIDS vaccine strategy are discussed. © 2011 Faculty of 1000 Ltd.