Objective: To investigate the occurrence of a gene-environment interaction between glutathione transferase (GST) gene polymorphisms (GSTM1, GSTT1, GSTP1, and GSTA1) and serum polychlorinated biphenyls (PCBs) levels. This is suggested as possible risk factors for endometriosis, a multifactorial gynecological disease. Design: Case-control study conducted from 2002 to 2005. Setting: Policlinico Umberto I, "Sapienza" University of Rome and Italian National Institute for Health, Rome. Patient(s): Italian women (N = 343), with laparoscopic diagnosis and histologic confirmation of the presence (cases, N = 181) or the absence (controls, N = 162) of endometriosis. Intervention(s): Genomic DNA extraction, multiplex polymerase chain reaction (PCR), and restriction fragment length polymorphism analysis. Determination of serum concentrations of selected PCBs by ion-trap mass spectrometry (subgroup, 63 cases and 63 controls). Main Outcome Measure(s): Endometriosis diagnosis by laparoscopy, GST genotypes, serum PCB levels. Result(s): The genotype distributions of GSTM1, GSTA1, and GSTP1 did not show any statistically significant difference between cases and controls. The GSTT1 null genotype was negatively associated with the disease. The GSTP1 wild-type genotype in the presence of medium-high blood levels of PCB153, total PCBs, or of high levels of PCB180 significantly increased the risk of endometriosis, suggesting a multiplicative interaction. Conclusion(s): The GSTs polymorphisms per se do not increase the risk of developing endometriosis. However, a gene-environment interaction was observed for GSTP1Ile/Ile and GSTM1 null genotypes, modulating the effect of PCB153, PCB180, and of total PCBs on disease risk. © 2012 American Society for Reproductive Medicine, Published by Elsevier Inc.