Objective: To estimate the effectiveness of enoxaparin-a low-molecular-weight heparin with antiheparanase properties-in treating localized provoked vulvodynia. Methods: Forty women with severe localized provoked vulvodynia were randomly and blindly assigned to self-administer either 40 mg enoxaparin or saline subcutaneously for 90 days. Dyspareunia and local sensitivity were evaluated before, at the end, and 90 days after treatment. The most painful focus was biopsied at the beginning of the study and a parallel site at the end of study for mast cells, PGP 9.5 nerve fiber staining, and heparanase quantification. Results: The enoxaparin-treated women showed a greater reduction in vestibular sensitivity at the end of treatment and 3 months later (29.6% compared with 11.2%, P=.004). Seventy-five percent (15 of 20) of them reported more than 20% pain reduction compared with 27.8% (five of 18) in the placebo group (P=.004). Seven enoxaparin-treated women compared with three in the placebo group had almost painless intercourse at the end of the study. In women who had improvement of sensitivity at the site parallel to the original biopsy site, there was a histologically documented reduction in the number of intraepithelial-free nerve fibers in the enoxaparin group. Conclusion: Enoxaparin reduced the vestibular sensitivity and dyspareunia, concomitant with a reduction in intraepithelial free nerve fibers, in women with localized provoked vulvodynia.