Supernatants from short-term cultures of placental or trophoblast-enriched cell suspensions derived from 14-17-day isopregnant mice display suppressive activity on NK lysis in vitro. The soluble factor is produced by trypsin-sensitive cells and requires protein synthesis. Its activity is destroyed by treatment with insoluble trypsin. The suppression is not strain restricted, but appears species-restricted. The factor acts at the level of the NK effectors themselves. Furthermore, such supernatants also are able to inhibit CTL-mediated lysis at the effector stage, in an MHC nonrestricted, nonspecific fashion. The effect is not seen with supernatants from control fetal tissues. At least two mechanisms could be involved: inhibition of homing toward allogeneic targets, and a direct effect on effector cell lytic action. These factors could play an important role in protecting the placenta from the deleterious effects of maternal antipaternal immunity and could explain the survival of the fetus in a presensitized maternal host.