Successful implantation requires a competent blastocyst and a receptive endometrium.   Endometrial receptivity is a state of endometrial differentiation marked by dramatic changes in the luminal epithelium and the stroma.  Protein convertase 5/6 (PC6) is up-regulated in the human endometrium specifically at the time of epithelial receptivity.  PC6 is a serine protease of the PC family that plays an important role in converting precursor proteins into their active forms by specific cleavage. Platelet derived growth factor A (PDGFA) requires PC cleavage for activation and the active form of PDGFA is secreted as a dimer (~30kDa). PDGFA is necessary for blood vessel development and cytoskeleton reorganisation; it is also known to be involved in the communication between the mother and embryo. This study identified an important role of PC6 in cleaving PDGFA during the establishment of endometrial receptivity.  To prove this, PC6 was specifically knocked down in an endometrial epithelial cell line, HEC1A, by stable transfection with siRNA specific to human PC6 (PC6-siRNA) or scrambled sequence (control).  PC6-siRNA cells are significantly less receptive than control. Western blot analysis showed an accumulation of PDGFA precursor but a reduction of the active form in PC6-siRNA cells than control.  Immunohistochemical analysis showed very different localisation of PDGFA in the human endometrium in the non-receptive versus receptive phase of the menstrual cycle. In the non-receptive phase, PDGFA was localised around the blood vessels and spiral arterioles, and the basement and cytoplasmic compartments of the glandular epithelium. In contrast, in the receptive phase, PDGFA was localised to the apical surface of the glandular and luminal epithelium.  These results suggest that PC6 regulates the cleavage/activation of PDGFA in the endometrial epithelial cells and that PDGFA localises to the apical surface of the epithelium during endometrial receptivity.