ABSTRACT: Prostaglandins, steroids, and their metabolites that are known to be produced by the conceptus, maternal endometrium, and placenta of the cow and sheep were tested for their ability to inhibit in vitro blastogenesis of bovine and ovine lymphocytes. Prostaglandin E2 (PGE2) suppressed PHA- and mixed lymphocyte reaction-induced blastogenesis in a log-linear, concentration-dependent manner, exerting its inhibitory effect at a final concentration of 10−8 M and higher. PGE2 also inhibited IL-2 -dependent proliferation of lymphocytes, but to a lesser degree than for PHA-treated cultures. Progesterone and estradiol-17β also inhibited [3H] thymidine incorporation into PHA-stim-ulated lymphocytes, but only at a pharmacological concentration of 10−5 M. No synergy between PGE2and progesterone in inhibiting lymphocyte proliferation was observed. Estrone, PGF2α, 15-keto-13,14-dihydro-PGF2α, and two metabolites of progesterone (5β-preg-nane-3,20-dione and 5β-pregnane-3,20-diol) had no effect on lymphocyte proliferation. By virtue of its continual production at the fetal-maternal interface throughout pregnancy, PGE2 may be an important local immunoregulatory agent to protect the allogeneic fetus from maternal immunological attack in the cow and ewe.