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Background: Previous studies usually focused on the separate association of metabolism or genetic factors with lung cancer risk and have largely ignored their combined effect. We aimed to examine the associations between serum lipid levels, genetic risk, and lung cancer risk. Methods: A total of 426,524 participants of the UK Biobank were included. The Cox proportional hazards models and restricted cubic splines were performed to assess the association between serum lipid and lung cancer risk. Polygenic risk score (PRS) was constructed to assess its joint effect and interaction with serum lipid on lung cancer risk. Results: Higher level of apolipoprotein A was significantly correlated with lower lung cancer risk. An inverse-J-shaped relationship between high-density lipoprotein (HDL) and incident lung cancer was found. Individuals with low total cholesterol, HDL, low-density lipoprotein (LDL), apolipoprotein A, and apolipoprotein B, combined with high PRS, showed significantly elevated lung cancer risks. Compared to those with low PRS and low triglycerides, participants with high PRS and elevated triglyceride levels had a notably higher risk. The interaction effect of high PRS and low LDL [relative excess risk due to the interaction (RERI): 0.25, 95% confidence interval, 0.04-0.46], as well as the interaction effect of high PRS and low apolipoprotein B (RERI: 0.28, 95% confidence interval, 0.07-0.48), were both greater than the sum of their individual effects on lung cancer risk. Conclusions: Serum lipids were associated with lung cancer risk. LDL or apolipoprotein B interacting with genetic risk may affect lung cancer risk. Impact: Our findings emphasize the need for individuals with heightened genetic risk should pay more attention to their lipid levels to reduce lung cancer risk. [ABSTRACT FROM AUTHOR]