The effect of human pregnancy plasma on phytohemagglutinin-(PHA-)induced blastogenesis of lymphocytes from unrelated donors was studied in relation to the sialic acid (N-acetyl-neuraminic acid) content of the plasma. The total sialic acid levels in plasma were found to be elevated during pregnancy as compared with plasma from non-pregnant, normally menstruating control groups (p less than 0.001) and to increase with advancing gestation, reaching peak values in the post-partum period (1-14 days). On the other hand, pregnancy plasma at a concentration of 15% caused a significant suppression of lymphocyte proliferation (p less than 0.05 to p less than 0.001, depending on the stage of gestation). The maximum effect was observed with plasma obtained during the third trimester of pregnancy. The immunosuppressive activity was not detectable after parturition. It was further observed that desialation of both pregnancy and control plasma with neuraminidase diminished lymphocyte response to PHA (p less than 0.05). Addition of free sialic acid (0.1-1.0 mumol/ml) or treatment of the cells with neuraminidase (0.06-1.0 IU/ml) had no effect on lymphocyte transformation under assay conditions. These findings support the hypothesis that an immunosuppressive environment provided by pregnancy plasma could be one of the mechanisms protecting the antigenically alien fetus from maternal immunologic attack. The sialic acid content of maternal plasma did not appear to play a role in the immunosuppressive property of maternal plasma. On the contrary, the presence of plasma-bound sialic acid in the culture medium was found to be necessary for normal lymphocyte reactivity.