Endometriosis is a common gynecologic disease characterized by the ectopic growth of endometrial tissue. In industrialized countries, it affects approximately 10% of women of reproductive age. Its etiology is unclear, but a multifactorial origin is considered to be most plausible. Environmental organochlorinated persistent pollutants, in particular dioxins and polychlorinated biphenyls (PCBs), have been hypothesized to play a role in the disease etiopathogenesis. However, results of studies carried out on humans are conflicting. We evaluated the exposure to organochlorinated persistent pollutants as a risk factor for endometriosis. We conducted a case-control study in Rome on 158 women comprising 80 cases and 78 controls. In all women, serum concentrations of selected non-dioxin-like PCBs (NDL-PCBs) and dioxin-like PCBs (DL-PCBs), 1,1-dichloro-2,2,-bis(4-chlorophenyl)-ethene (p,p'-DDE), and hexachlorobenzene (HCB) were determined by ion-trap mass spectrometry. DR-CALUX bioassay was employed to assess the 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity equivalent (TEQ) concentrations of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and DL-PCBs. We found an increased risk of endometriosis for DL-PCB-118 [odds ratio (OR) = 3.79; 95% confidence interval (CI), 1.61-8.91], NDL-PCB-138 (OR = 3.78; 95% CI, 1.60-8.94), NDL-PCB-153 (OR = 4.88; 95% CI, 2.01-11.0), NDL-PCB-170 (OR = 3.52; 95% CI, 1.41-8.79), and the sum of DL-PCBs and NDL-PCBs (OR = 5.63; 95% CI, 2.25-14.10). No significant associations were observed with respect to HCB or to the sum of PCDDs, PCDFs, and DL-PCBs given as total TEQs. The results of this study show that an association exists between increased PCB and p,p'-DDE serum concentrations and the risk of endometriosis.