Embryo implantation requires two critical factors: a synchronously developed healthy embryo and a receptive endometrium. The development of a receptive endometrium is highly regulated, were by the endometrial epithelium undergoes considerable morphological and physiological changes during the mid-secretory phase of the menstrual cycle (known as the “window of implantation”). One fundamental aspect of receptivity establishment is the remodeling of the cell surface extracellular glycoprotein network to convert the endometrium to an adhesive state. We have established that proprotein convertase 5/6 (PC6) is a critical endometrial regulator for receptivity. PC6 is up-regulated in the endometrial epithelium specifically during the receptive phase in women and endometrial epithelial dys-regulation of PC6 is associated with infertility. Using a unique HEC-1A cell line in which PC6 is stably knocked by siRNA and human endometrial tissues, we discovered in this study that PC6 regulated receptivity through cleaving a large cell surface glycoprotein/adhesion molecule, dystroglycan (DG). DG consists of two subunits α and β-DG, derived from a single gene product. While β-DG is anchored within the membrane, α-DG attaches to β-DG extra-cellularly and mediates adhesion. Specifically, the central glycosylated part of α-DG mediates adhesion. However, this region is masked by its large 312 amino acid (aa) N-terminus (α-DG-N). Our study discovered that PC6 cleaved α-DG to remove α-DG-N, thus exposing the central region of α-DG to make the endometrium more adhesive for embryo attachment. In addition, α-DG-N cleaved from the membrane is present in the conditioned media of endometrial epithelial cells and in uterine fluids of women, and importantly its levels correlate with receptivity status. This study thus identified new and exciting insights into PC6 function in receptivity establishment. Our data also strongly suggests that α-DG-N in uterine fluids of women may be a potential biomarker for diagnosing receptivity.