Background: Successful pregnancy inevitably depends on the implantation of a competent embryo into a receptive endometrium. Although a remarkable improvement of assisted reproductive technology (ART) has been achieved over the last few decades, there are still a number of infertile women experiencing frequent ART failure after repeated attempts due to many unsolved problems including repeated failure of implantation. Many substances have been suggested to improve the rates of embryo implantation by enhancing the endometrial receptivity for the patients who are suffering from repeated failure of implantation. However, despite these numerous extensive research work, there are currently no effective evidence-based treatments to prevent or cure this condition. Therefore, here we aim to suggest non-invasive intra-uterine administration of embryo-secreted chemokine CXCL12 as an effective therapeutic intervention to solve this problem.Results: We demonstrated that chemokine CXCL12 is derived from pre- and peri-implanting embryos and its interaction with endometrial CXCR4 and CXCR7 enhances endometrial receptivity and significantly promoted endothelial vessel formation and sprouting in vitro. Consistently, intra-uterine CXCL12 administration in vivo, which is a completely non-invasive treatment strategy, improved endometrial receptivity showing increased integrin b3 and its ligand osteopontin, and induced endometrial angiogenesis displaying increased numbers of vessel formation near the lining of endometrial epithelial layer with higher CD31 and CD34 expression. Furthermore, intra-uterine CXCL12 application dramatically promoted the rates of embryo implantation with no morphologically retarded embryos. Conclusions: Our present study provides a novel evidence that improved uterine endometrial receptivity and enhanced angiogenesis induced by embryo-derived chemokine CXCL12 may aid to develop a non-invasive therapeutic strategy for clinical treatment or supplement for the patients with repeated implantation failure with less risk.