Although activation of the nuclear progesterone (P(4)) receptor (PGR) is required for uterine function, some of the actions of P(4) are mediated through a PGR-independent mechanism. The receptors that account for the PGR-independent actions have not been identified with certainty. The purpose of this study was to assess the expression, localization and hormonal regulation of two novel P(4) receptor candidates, P(4) receptor membrane component (PGRMC) 1 and PGRMC2, as well as the PGRMC1 partner Serpine 1 mRNA binding protein (SERBP1). Unlike Pgrmc1 and Serbp1, which remained unchanged throughout the estrous cycle, Pgrmc2 was highly up-regulated during proestrus and metestrus. Immunohistochemical analyses suggest that PGRMC1 and SERBP1 promote differentiation, since the expression of these proteins increased in endometrial cells undergoing steroid-depended terminal differentiation. Progesterone rather than estrogen appears to be primarily responsible for up-regulating the expression of PGRMCs. PGRMC1 and SERBP1 also showed overlapping patterns of expression in the human placenta and associated membranes with the most abundant expression in smooth muscle of the placental vasculature, villous capillaries and the syncytiotrophoblast. Based on these findings, it is proposed that PGRMC1:SERBP1 protein complex functions in events important to early pregnancy including cellular differentiation, modulation of apoptosis and steroidogenesis. These studies provide a platform from which to build a clearer understanding of P(4) actions in the female reproductive tract and placental tissues that are mediated by non-classical mechanisms.