Objectives: The purpose of this study was to evaluate whether oral contraceptives (OCPs), Levonorgestrel (LNG) intrauterine devices (IUDs), and Copper IUDs block the up-regulated expression of the L-selectin ligand to determine if this mechanism of action makes feasible a non-hormonal, highly effective “on demand” contraceptive. Methods: We studied L-selectin expression in the endometrium of women in four groups: (1) LNG-IUD users n=9, (2) copper-IUD users n=13, (3) LNG-OCPs users n=10 and (4) controls n=11. Endometrial biopsies were collected during the luteal phase of ovulatory cycles for IUD users and controls. L-selectin expression was evaluated using the antibody MECA-79. We compared MECA-79 staining of the endometrium of women in each group to endometrium from controls. A semiquantitative immunohistochemical scoring was used to grade endometrial staining based on the intensity of the staining: 0 (no staining) to 4 (uniform, intense staining). Results: Mean staining scores were controls=3.08 (SD 0.94), Copper IUD users=2.85 (SD 0.99), OCP users=1.3 (SD 1.06), and LNG- IUD users=0.67 (SD 0.87) (p<0.001). Conclusion: Our results indicate that Copper IUDs have no effect on endometrial expression of L-selectin compared to controls, whereas the two forms of contraception containing LNG result in a significant decrease in L-selectin expression. Given the divergent effects of the two types of IUDs, our results suggest that IUDs do not share a common pathway on endometrial receptivity to implantation. LNG, whether delivered locally or systemically, may act in part by altering endometrial expression of L-selectin to inhibit implantation along with the cervical and ovarian actions that reduce the probability of fertilization.