Although some persistent organic pollutants (POPs) may not be currently in production, many of these chemicals still exist ubiquitously in the environment and continue to represent significant environmental health concern. One of the important concerns of POPs exposure may lead to the adverse reproductive consequences including primary ovarian insufficiency (POI), but the limited evidence has been reported so far. Our case-control study was performed to explore the association between serum levels of selected POPs and risk for POI in a Chinese female population, including 157 cases and 217 healthy controls. Serum concentrations of polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), polybrominated diphenyl ethers (PBDEs) and serum levels of reproductive hormones [follicle-stimulating hormone (FSH), luteinizing hormone (LH), anti-Mullerian hormone (AMH) and estradiol] were measured. The medians of dioxin-like PCBs (DL-PCBs) and p,p'-dichlorodiphenyltrichloroethane (p,p'-DDT) were significantly higher in case sera than in controls. Higher concentrations of DL-PCBs and p,p'-DDT were significantly associated with elevated risk of POI. A dose-response relationship was observed between the sum of DL-PCBs (Σ6 DL-PCBs) and the risk of POI (p for trend = 0.003), with odds ratios for the second and third tertiles, compared with the first, of 1.31- (95% CIs: 0.67-2.57) and 3.15-fold (95% CIs: 1.63-6.10), respectively. Similar results were observed for the sum of p,p'-DDT and its metabolites (Σ2 p,p'-DDTs). In control women, FSH levels were negatively associated with PCBs exposure, while LH had a positive association with OCPs. In patients with POI, exposure to PCBs was correlated with higher levels of LH, whereas exposure to OCPs was associated with lower levels of AMH. To the best of our knowledge, this study for the first provided evidence that exposure to PCBs and DDT could be the potential risk factors for POI in women.