We investigated the associations between lung cancer and the gene polymorphisms of the drug metabolizing enzymes, containing cytochrome P450 1A1 (CYP1A1), cytochrome P450 1A2 (CYP1A2), glutathione S-transferase class mu (GSTM1), and N-acetyltransferase 2 (NAT2). The study involved 113 lung cancer patients and 121 non-cancer controls divided into never, light and heavy smokers according to pack-years of smoking in Japanese by using PCR-RFLP. For light smokers, the lung cancer risk of NAT2 intermediate-slow was significantly increased [the adjusted odds ratio (OR): 10.9, 95% confidence intervals (95%CI): 1.75-67.5, P-value: 0.010]. Moreover, never smokers having joint genotypes of NAT2 intermediate-slow and CYP1A2*1F A/A was also associated with increased the lung cancer risk (OR: 4.95, 95% CI: 1.19-20.6, P-value: 0.028). We suggested that light smokers with intermediate-slow NAT2 activity were at highest risk for lung cancer and the gene-gene interaction based on intermediate-slow NAT2 activity and high CYP1A2 activity would be increased a lung cancer risk among never smokers.