When activated with the mitogenic lectin, concanavalin A, a subset of human peripheral blood mononuclear cells differentiate into potent suppressor cells that negatively modulate both cellular and humoral immune reactions. In addition to inhibitory cell-cell interactions, these regulatory cells elaborate a soluble immune suppressor supernatant (SISS) containing at lest 2 distinct suppressor factors. One of these factors, SISS-T, inhibits mitogen- and antigen-stimulated T cell proliferation, whereas the other, SISS-B, inhibits B cell immunoglobulin production. Characteristics of the latter inhibitor are reported in the companion paper. Properties of the soluble suppressor of T cell proliferation (SISS-T) include: 1) a m.w. of 30 to 45,000, 2) inhibition by a noncytotoxic mechanism, 3) instability at 56 degrees C, 4) loss of activity in the presence of the monosaccharide N-acetyl-D-glucosamine and retention on N-acetyl-D-glucosamine affinity columns, 5) binding to the same surface glycoprotein receptors recognized by the lectins wheat germ agglutinin and Agaricus bisporus lectin, which produce similar inhibition of mitogen- or antigen-induced lymphocyte proliferation, 6) elaboration by cells irradiated with 500 and 2000 R but not 6000 R, 7) a minimum requirement for 24 hr of lectin stimulation for production, and 8) elaboration by adherent cells or alternatively cellular collaboration requiring the participation of adherent cells. These data indicate that human suppressor cells are capable of modulating T cell function via the production of a soluble saccharide-specific factor(s) that interacts with defined surface glycoprotein or glycolipid receptors. These same receptors recognized by the suppressive endogenous lectin are also activated by selected exogenous nonmitogenic lectins that produce similar inhibition of T cell metabolism.