In ruminants, the corpus luteum (CL) of early pregnancy is resistant to luteolysis. PGE₂ is considered as a luteoprotective mediator. Early studies indicate that during the establishment of pregnancy in sheep, a factor(s) from the conceptus or gravid uterus reaches the ovary locally through the utero-ovarian plexus (UOP) and protects the CL from luteolysis. The local nature of the embryonic antiluteolytic or luteoprotective effect precludes any direct effect of a protein transported or acting between the gravid uterus and CL in ruminants. At the time of establishment of pregnancy, interferon tau (IFNT) secreted by the trophoblast of the conceptus inhibits endometrial pulsatile release of PGF2a and increases endometrial PGE2. Our recent studies indicate that (1) luteal PG biosynthesis is selectively directed toward PGF2a at the time of luteolysis and toward PGE₂ during establishment of pregnancy; (2) the ability of CL of early pregnancy to resist luteolysis is likely due to increased intraluteal biosynthesis of PGE₂ and signaling; (3) IFNT protein is not transported from the uterus to the CL through the UOP vascular route; and (4) a large proportion of endometrial PGE₂ is transported from the uterus to the CL through the UOP vascular route during the establishment of pregnancy in sheep. Our ongoing studies indicate that intrauterine co-administration of IFNT and PGES-1 inhibitor inhibits IFNT action and IFNT fails to rescue the CL in cyclic sheep. By contrast, intrauterine co-administration of IFNT and PGES-1 inhibitor along with intraovarian administration of PGE2 rescues the CL in cyclic sheep. These results suggest that IFNT may prolong the lifespan of the CL by increasing endometrial secretion of PGE₂ which in turn increases luteal PGE₂ biosynthesis and signaling and promotes luteal resistance. Together, our studies provide compelling evidence that PGE2 produced by the CL in response to endometrial PGE2 may protect the CL, as a component of luteoprotective mechanisms, at the time of maternal recognition of pregnancy in ruminants. These novel findings may offer therapeutic strategies to target PGE2 biosynthesis and signaling selectively in the endometrium and/or CL to improve reproductive efficiency in ruminants.