Increased prostaglandin E(2)(PGE(2)) synthesis involves multiple enzymes and two isoforms of the terminal enzyme of this biosynthetic pathway, PGE synthase (PGES), were recently identified. Cytosolic PGES (cPGES) is identical to the Hsp90 chaperone, p23, and is reportedly functionally coupled to constitutive PG endoperoxide H synthase-1 (PGHS-1). Microsomal PGES (mPGES), on the other hand, is inducible by proinflammatory cytokines such as IL-1beta. We have studied the cellular localization of both enzyme isoforms in human placenta at term and early gestation (10 weeks). Cytosolic PGES was immunolocalized to the fibroblasts and macrophages in villous stroma, whereas mPGES was localized in the extravillous trophoblasts (EVTs) as well as macrophages in both term and early gestation tissues. Microsomal PGES was also observed in cytotrophoblasts (CTs), but not in syncytiotrophoblasts (STs), in early gestation. Apoptotic early gestational STs were heavily stained with cPGES. We also investigated the cellular localization of cPLA(2)and PGHS-2 in early gestation and at term. Cytosolic PLA(2)was immunolocalized to the stroma and STs at term, but was only observed in CTs in early gestation. PGHS-2, on the other hand, was immunolocalized to both extravillous and STs in early gestation and at term. Our results suggest that mPGES could play a role in trophoblast invasion via its association with EVTs in the basal plate, whereas cPGES could be involved in apoptosis or repair mechanisms.