The immunosuppressive activity of a JEG-3 choriocarcinoma-derived factor in human IL-2-dependent T cell responses has been studied, together with its effect on IL-2-independent T cell responses induced by 10 nM TPA. The factor completely suppressed the IL-2-independent proliferative responses of T cells but failed to suppress antigenic expression of activation-associated CD 25 molecules. Further studies examined the effect of the factor on LAK cell generation induced by rIL-2. Recombinant IL-2-induced LAK cell proliferation was observed on Day 4 and Day 5, but not on Day 3. As the factor suppressed the responses of LAK cell proliferation, we tested whether it blocked the generation of Day 3, Day 4 and Day 5 LAK cells. The addition of the factor failed to suppress the generation of Day 3 LAK cells, while it partially suppressed the lytic activity of Day 4 LAK cells and completely suppressed that of Day 5 LAK cells. The data suggest the presence of a heterogeneous pattern for LAK cell generation; one without proliferation, but the other requiring proliferation, to acquire killer activity. Taken together with the evidence that the factor failed to suppress NK activity, the choriocarcinoma-derived factor suppressed only the proliferative events of immunocompetent cells, but inhibited neither their activation nor the differentiation events. This immunosuppressive factor might be involved in the prevention of host-mediated rejection of choriocarcinoma cells or maternal rejection of the fetus.