Cellular proteins associated with immunodeficiency viruses were identified by determination of the amino acid sequence of the proteins and peptides present in sucrose density gradient-purified human immunodeficiency virus (HIV)-1, HIV-2, and simian immunodeficiency virus (SIV). β2 microglobulin (β₂m) and the α and β chains of human lymphocyte antigen (HLA) DR were present in virus preparations at one-fifth the concentration of Gag on a molar basis. Antisera to HLA DR, β₂m, as well as HLA class I precipitated intact viral particles, suggesting that these cellular proteins were physically associated with the surface of the virus. Antisera to class I, β₂m, and HLA DR also inhibited infection of cultured cells by both HIV-1 and SIV. The specific, selective association of these cellular proteins in a physiologically relevant manner has major implications for our understanding of the infection process and the pathogenesis of immunodeficiency viruses and should be considered in the design of vaccines.