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There is convincing evidence that soluble HLA-A,-B,-C (sHLA-A,-B,-C) and soluble HLA-G (sHLA-G) antigens can induce apoptosis in CD8+ activated T 3;cells although there is scanty and conflicting information about the mechanism(s) by which sHLA-A,-B,-C antigens and sHLA-G antigens induce apoptosis. In this study we have compared the apoptosis-inducing ability of sHLA-A,-B,-C antigens with that of sHLA-G1 antigens in CD8+ T 3;lymphocytes and CD8+ NK cells. Furthermore we have compared the inhibitory effect of sHLA-A,-B,-C antigens and of sHLA-G1 antigens on theactivity of EBV-specific CD8+ cytotoxic T lymphocytes (CTL). sHLA molecules were purified from serum and from the supernatant of HLA class 3;I-negative cells transfected with one gene encoding either classical or non-classical HLA class 3;I antigens. Both classical and non-classical sHLA class 3;I molecules trigger apoptosis in CD8+ T 3;lymphocytes and in CD8+ NK cells, which lack the T 3;cell receptor, and their apoptotic potency is comparable. The binding of sHLA-A,-B,-C and sHLA-G1 molecules to CD8 leads to Fas ligand (FasL) up-regulation, soluble FasL (sFasL) secretion and CD8+ cell apoptosis by Fas/sFasL interaction. Moreover, classical and non-classical sHLA class 3;I molecules inhibit the cytotoxic activity of EBV-specific CD8+ CTL. As the amount ofsHLA-G molecules detectable in normal serum is significantly lower than that of sHLA-A,-B,-C molecules, the immunomodulatory effects of sHLA class 3;I molecules purified from serum are likely to be mainly attributable to classical HLA class 3;I antigens. As far as the potential in vivo relevance of these findings is concerned, we suggest that classical sHLA class 3;I molecules may play a major immunoregulatory role in clinical situations characterized by activation of the immune system and elevated sHLA-A,-B,-C serum levels. In contrast, non-classical HLA class 3;I molecules may exert immunomodulatory effects in particular conditions characterized by elevated sHLA-G levels such as pregnancy and some neoplastic diseases.