Abstract Background Polychlorinated biphenyls (PCBs) are endocrine-disrupting chemicals that have been associated with various adverse health conditions. However, the interaction effects between PCBs, lifestyle, and/or genetic susceptibility on dyslipidemias are still unknown. Methods Six serum PCBs including PCB-28, 101, 118, 138, 153, and 180 were determined in 3,845 participants from the Wuhan-Zhuhai cohort. Dyslipidemias, including hyper-total cholesterol (HyperTC), hyper-triglyceride (HyperTG), hyper-low density lipoprotein cholesterol (HyperLDL-C), and hypo-high density lipoprotein cholesterol (HypoHDL-C) were classified based on serum lipids levels, which were examined by an automatic biochemical analyzer. Besides, we constructed lipid-specific polygenic risk scores (PRS) and healthy lifestyle scores, and used Logistic regression models to explore the relationships of serum PCBs, lifestyle, and PRS with dyslipidemias. Results We observed that all six PCB congeners were positively associated with the prevalence of dyslipidemias to varying degrees. In particular, dose-response manners were observed between ΣPCB levels and odds ratios (ORs) of HyperTC, HyperTG, and HyperLDL-C, respectively. Besides, we found that PRSs and unhealthy lifestyles were both positively associated with dyslipidemias. For the combined effect of ΣPCB, lifestyle, and PRS, participants with high ΣPCB, unfavorable lifestyle, and high genetic risk had the highest odds of HyperTC (2.285; 1.533, 3.417), HyperTG (7.944; 5.169, 12.329), and HyperLDL-C (3.523; 2.311, 5.394) when compared with those with low ΣPCB, healthy lifestyle, and low genetic risk. Conclusions Our study provided evidence that PCB exposure potentially increases the prevalence of dyslipidemias, which may be exacerbated by genetic susceptibility and unhealthy lifestyles. Key messages • Our results highlighted the importance of reducing PCB exposure, adopting healthy lifestyles for the prevention of dyslipidemia. • Our work might facilitate the emergence of reducing or regulating PCB pollution to control blood lipids and the resultant dyslipidemia epidemic.