Lung cancer is one of the most common malignant tumors that seriously threaten human health. Current evidence suggests that heredity contributes to the progression of lung cancer. To investigate and validate potential genetic associations with the risk of lung cancer, we conducted a case-control study including 309 cases and 310 controls from Xi'an City, which is located in northwest China, and genotyped six SNPs in five genes, which are related to metabolic process. Overall, our results show that the SNP rs10937405 was associated with a decreased occurrence of lung cancer (OR = 0.72; 95% CI = 0.56-0.92; p = 0.009). In the genetic models analysis, we found that genotype "CT" of rs10937405 in TP63 was associated with a decreased lung cancer risk (OR = 0.71; 95% CI, 0.51-0.99; p = 0.031); the genotype "TT" of rs10937405 showed a decreased lung cancer risk in the co-dominant model (OR = 0.53; 95% CI, 0.30-0.95; p = 0.031). The genotype "CT-TT" of rs10937405 also showed a decreased lung cancer risk in the dominant model (OR = 0.67; 95% CI, 0.49-0.92; p = 0.014) and the log-additive model (OR = 0.72; 95% CI, 0.56-0.92; p = 0.0085). The genotype "CC-CT" of rs10937405 confers a higher risk of lung cancer for males than females. Our results, combined with those from previous studies, suggest that genetic variation in TP63 may influence lung cancer susceptibility in the Han population.