The effect of pregnancy zone protein (PZP), which exhibits increased levels in the blood during pregnancy, on T cells was examined. PZP was found to suppress DNA synthesis following stimulation with phytohemagglutinin (PHA), concanavalin A (ConA) or CD3 antigen or in the mixed lymphocyte reaction (MLR). This effect of PZP was mediated by a reduction in interleukin-2 (IL-2) production, and was abolished by exogenous recombinant IL-2 administration. PZP did not affect the proliferation of T cells following stimulation with the calcium ionophore A23187 and phorbol 12-myristate 13-acetate (TPA). These results suggest that PZP acts on the T cell surface and reduces IL-2 production, but not IL-2R expression, and does not directly affect Ca2+ influx or protein kinase C.