A B S T R A a . We examined normal human placenta for an immunologic function by measuring the release of soluble inhibitory factor (SIF). SIF is a product of normal T lymphocytes and of the JEG-3 choriocarcinoma cell line, and blocks proliferative and antibody-producing responses of mononuclear cells. SIF can be further characterized by a noncovalently linked subcomponent, lipid suppressor substance. The villous surfaces of six normal human placentae were digested with collagenase to obtain a population of predominantly multinucleated giant cells. These cells were maintained in standard culture for 5 days after which the cell-free conditioned culture medium was assayed for SIF content by measuring suppression of VH] thymidine incorporation into lymphocytes stimulated by low-dose phytohemagglutinin. Undiluted placental SIF induced 88% inhibition of this response (p < 0.001). The placental SIF was found to contain lipid suppressor substance, as does SIF from mononuclear cells. We determined this by thin-layer chromatography where a peak of suppressive activity occurred at Rf 0.32 (PHjthymidine incorporation reduced from 21810 + 308 to 4121 2 214 cpm); this is the position on thin-layer chromatography to which mononuclear cell lipid suppressor substance migrates. Ion exchange chromatography comparing the elution patterns of lymphocyte-SIF and placental-SIF indi: cated that both eluted in the fraction of 40-50 mM P W buffer, further suggesting identity between these two substances. SIF from placental and lymphocyte sources functioned by inducing the presence of suppressor cells in culture. Mononuclear cells were incubated for 48 h in SIF; the resultant cell population reduced [H3]thymidine incorporation into phytohemagglutinin-stimulated lymphocytes from 21170 + 1721 to 8612 2 311 cpm (60% inhibition, p < 0.001). Adherent cells were not required for function of these cells and they were not sensitive to mitomycin C. The placenta helps prevent immunologic rejection of the fetus by several mechanisms; it functions as a barrier, it is devoid of human histocompatibility leukocyte antigen markers and it has immunologic functions. The studies presented herein indicate that the placenta releases a substance that induces the formation of suppressor cells. These data support the hypothesis that placental cells have an immunoregulatory function. (Pediatr Res 23: 212-218, 1988) Abbreviations Ec, effector cells FCS, fetal calf serum PH]TdR, tritiated thymidine