Understanding how P4 signaling occurs in endometrial cells is important to guide the development of more effective therapeutic approaches to the numerous reproductive diseases caused by disrupted P4 signaling, resulting in subfertility or infertility (Bunch et al., 2013; Kim et al., 2013; Zhang and Murphy, 2014; Szekeres-Bartho, 2018; Hirota, 2019; Liao et al., 2019). Here, to fill these knowledge gaps, we characterized endometrial PGRMC2 expression throughout the human menstrual cycle and in hEnSCs subjected to an in vitro model of human endometrial decidualization. Additionally, we describe the functional implications of PGRMC2 with a silencing approach assay, integrating RNA-seq and proteomic techniques. We evaluated the functional implication of PGRMC2 in the embryo implantation process with an outgrowth in vitro model. Finally, we also compared endometrial PGRMC2 expression with PGRMC1 and PGR.