In this study the presence of a highly immunogenic domain located at the C-terminus of the external glycoproteins (EGP) of human and simian immunodeficiency viruses (HIV-1, HIV-2, and SIVMAC) is shown using synthetic oligopeptides as antigens in enzyme immunoassays. This epitope is probably located within the last 13 and 15 residues of the EGP of HIV-1 and HIV-2, respectively. The C terminal epitope of the EGP of SIVMAC may involve residues located more upstream. Among the HIV-2/SIV serotype, we observed that the reactivity to the C-terminal epitope of gp120 was dependent of both species and geographical origin of the samples tested. It seems that this gp 120 C-terminal epitope could distinguish subtypes among the HIV-2/SIV serotype. Further studies, using site-directed enzyme immunoassays with synthetic peptides representing the C-terminus of the EGP derived from a wide variety of HIV2/SIV strains must be performed to confirm this observation. These kinds of assays may constitute important tools for use in seroepidemiological studies and broaden our understanding of the distribution and phylogenetic relationship of primate lentiviruses.