BACKGROUND This study was designed to investigate leptin levels in the fluid in ovarian endometriomas (OEs) and to compare the expression of leptin and its receptors (OBR) in ovarian tissue affected by endometrioma in infertile women to its expression in the normal ovarian tissue of fertile controls without endometriosis. METHODS In this case-control observational study, ovarian tissue, blood samples and peritoneal fluid were obtained from 20 women (10 fertile controls without endometriosis or any ovarian disease, who were undergoing tubal ligation surgery, and 10 infertile women with severe endometriosis and OE). The ovarian endometriomal fluid (EF) was aspirated, and peritoneal-implant (PI) biopsies were performed. The tissues removed during the surgeries were immediately frozen in liquid nitrogen to determine expression levels by western blot and leptin levels by ELISA. RESULTS OBR was expressed at higher levels in the ovarian tissue affected by endometrioma than in the normal ovarian tissue (control = 0.38 ± 0.05, study = 0.60 ± 0.09, p = 0.03), but there was no significant difference in leptin levels between these groups (control = 0.57 ± 0.1, study = 0.35 ± 0.1, p = 0.18). Positive and significant correlations were observed between leptin and OBR in the OE (r = 0.85, p = 0.004) and in the PI (r = 0.87, p = 0.001). ELISA results demonstrate a greater leptin concentration within the EF compared with the serum and the PF (serum = 14.25 ± 1.63, PF = 5.98 ± 2.0, EF = 73.8 ± 16.2, p = 0.0001), but there was no correlation between these variables. A positive, significant and strong correlation was observed between PF leptin levels and the expression of leptin and OBR in PI (leptin: r = 0.78, p = 0.007/OBR: r = 0.68, p = 0.04) and between the EF leptin levels and the expression of leptin and OBR in the OE (leptin: r = 0.88, p = 0.008/OBR: r = 0.89, p = 0.005). CONCLUSIONS These data suggest that leptin may play an important role in the physiopathology of OE through a modulatory interaction with its active receptor.