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Abstract: Introduction: The limited information for effects of serum trace elements and genetic polymorphisms on lung cancer is available. Based on a hospital based case–control study, the epidemiological questionnaires were completed by face to face interview, and the gene polymorphisms were tested by RFLP–PCR, and serum trace metals were measured by atomic absorption spectrophotometer, and the data was analyzed by the logistic regressive models. Results: The high serum copper level (>1500ng/ml) or serum copper/zinc ratio (>1) was the risk factors of NSCLC (OR=3.10, 11.03, respectively), but the ORs of the higher serum Zn (>1200ng/ml), Se (>50ng/ml) or Cr3+ (>600ng/ml) for NSCLC were all significantly less than 0.20 (all p <0.01) indicating strong protection against NSCLC. While the OR of CYP 1A1 variants carriers with a higher serum Cu or Cu/Zn ratio level was around 3.38 and 12.59, respectively, the risk of CYP1A1 variants carriers with a higher serum Zn is 0.18, Se 0.04 or Cr3+ 0.28. Similarly, compared with the carriers of GSTM1 power with a lower serum Zn, Se or Cr3+, the OR of the carriers of GSTM1 null with a higher serum Zn, Se and Cr3+ was separately 0.16, 0.07 and 0.26, highlighting the protection against NSCLC. Conclusions: Our findings suggested that CYP1A1 or GSTM1 variants may significantly modify the associations between level of serum trace metals (Cu, Zn, Se or Cr) and NSCLC, indicating the intriguing pathogenesis of lung cancer. [Copyright &y& Elsevier]