Human endometrial stromal cells (ESCs) differentiate into decidual cells for the embryo implantation during the mid-secretory phase of the menstrual cycle. Decidualization is characterized by their enhanced production of IGF binding protein-1 (IGFBP-1) and prolactin (PRL), and transformation into more rounded cells. Progesterone (P4) receptor membrane component 1 (PGRMC1) is a member of a P4 binding complex implicated in female reproduction. In this study, we explored the physiological roles of PGRMC1 in the decidualization of human ESCs. Immunohistochemical analysis revealed that PGRMC1 was expressed in endometrial glandular and luminal epithelial cells and stromal cells throughout the menstrual cycle, but the expression was reduced in the secretory phase. In the in vitro study, treatment of ESCs with P4 and dibutyryl (db)-cAMP, which induces decidualization, repressed PGRMC1 expression. Both PGRMC1 knock-down using siRNA and inhibition using AG-205, an inhibitor of PGRMC1 promoted the db-cAMP-induced IGFBP-1 and PRL expression in ESCs. We also found that microRNA miR-98 was increased in the process of decidualization and transfection of miR-98 mimic into ESC repressed PGRMC1 expression. These findings suggest that the secretory phase-specific downregulation of endometrial PGRMC1 which is regulated in part by miR-98 may promote decidualization for the establishment of pregnancy.