Genetic variations in metabolic activation or detoxification enzymes have been thought to contribute to individual differences in lung cancer susceptibility. Genetic polymorphisms of NAD(P)H quinone oxidoreductase (NQO1), cytochrome P4501A1 (CYP1A1) and microsomal epoxide hydrolase (HYL1) have been associated with increased lung cancer risk in Asian populations. In the present study, the possibility of an association of NQO1, CYP1A1 and HYL1 genetic polymorphisms with lung cancer was examined among residents in Nanjing, China. A total of 84 lung cancer patients and 84 control subjects were matched by age, gender, occupation and smoking status. No significant association was observed for these genetic polymorphisms with the overall incidence of lung cancer. When the groups were stratified according to smoking status, we found that smokers carrying the HYL1*2 allele had a higher relative risk for lung cancer Odds ratio ((OR), 5.66; 95% confidence interval (95% CI), 1.71-18.68). The association was also found with squamous cell carcinoma (OR, 3.23; 95% CI, 1.00-10.38). Our results suggest that HYL1*2 polymorphism might be a risk factor for smoking-associated lung cancer in China.