Spleen cells from newborn to 2-day-old, but not 3-day-old or older, rats suppress the activity of cells from adult animals in xenogeneic local graft-versus-host (GVH) assay. The duration of neonatal suppressor cell activity can be significantly prolonged by treating newborn rats with exogenous prostaglandin E2 (PGE2), and the suppression was completely abolished by administration of PGE inhibitor indomethacin. The results thus demonstrate an involvement of PGE2 in the mechanism of action of neonatal suppressor cells and may explain some discrepancies concerning the nature of natural suppressor cells present in newborn animals.