Problem Patients with repeated implantation failure (RIF) represent a subgroup of couples who suffer from unexplained infertility. Human blastocysts utilize L-selectin to initiate implantation by binding to endometrial ligands composed of oligosaccharide moieties on the surface glycoproteins. The absence of these ligands could lead to recurrent implantation failure (RIF) in some of these couples. Methods Twenty fertile women and 20 patients with RIF were tested for the presence of the L-selectin ligands by immunohistochemistry. Endometrial biopsies were obtained on the sixth day post ovulation. After fixation, they were dated according to Noyes. Immunolocalization was performed using the MECA-79 antibody which is directed against ligands of L-selectin. Results The fertile group all showed the presence of the L-selectin ligand. Of those with RIF, five were negative for the ligand and never, despite an average of five successive embryo transfers, became pregnant. Fifteen RIF patients were positive for the L-selectin ligand, of whom ten subsequently conceived. As a screening test for RIF patients who lack the ligand, the predictive value was 100% with a sensitivity of 50% and specificity of 100%. The positive predictive value was 100% and negative predictive value is 87%. Conclusions L-selectin and its ligands play a vital role for early human implantation. Screening for the absence of the ligand may help many patients with RIF to avoid undergoing repeated failed treatment cycles.