Immunosuppression frequently accompanies infections with the human retroviruses HTLV-1 and HIV. Previous studies have shown that UV-inactivated and detergent-disrupted preparations of either virus can produce immune dysfunction in vitro although the active component of such preparations has not yet been identified. We now report that synthetic peptides corresponding to a conserved sequence within the transmembrane envelope proteins of both HTLV-1 (CS-1) and HIV (CS-3) are capable of suppressing the in vitro proliferative responses of human T lymphocytes to mitogenic or allogeneic stimulation. CS-1 inhibits proliferation in response to stimulation by anti-CD3 antibody by up to 57% a concentration of 3 nmol per culture well. CS-3 inhibits by up to 49% at a similar concentration. CS-1 and CS-3 inhibit two-way mixed leukocyte culture reactions by 81 and 88%, respectively, at the 3 nmol per well concentration. The inhibition by such human retrovirus-related peptides appears to be T cell-specific in that B cell proliferation in response to stimulation with anti-IgG is not affected by the CS-3 peptide. The release of such immunosuppressive peptides may thus play a role in the pathogenesis of human exogenous retroviral disease such as AIDS.