Genes for cytochrome P4501A1 (CYP1A1) and glutathione S-transferase class mu (GSTM1) have been shown to be polymorphic, and have been implicated in tobacco-related carcinogenesis. In the present study, the role of the combined genotypes CYP1A1 and GSTM1 as a possible modulator of smoking related lung cancers was studied in relation to the tobacco smoke exposure level in 118 Japanese patients aged < 70 with squamous or small cell carcinomas of the lung. Among male smoking patients, the overall proportion of the GSTM1 null genotype (GSTM1[-]) was slightly higher than among healthy male smoker controls (56.7% versus 48.1%, P = 0.17). Little difference was observed between smoker patients and corresponding controls in overall frequencies of m2 mutant allele homozygotes (CYP1A1[m2/m2]) (16-18%) and Val encoding allele homozygotes (5-6%). However, when subjects were categorized by both CYP1A1 genotype (MspI polymorphism) and GSTM1 genotype, GSTM1(-) became markedly more expressed in patients with CYP1A1(m2/m2) when compared to the corresponding smoker controls (81.3% versus 39.4%, P < 0.01). When odds ratios were estimated using nonsmoking patients and healthy controls as a reference, the relative risk for developing lung cancer was found to increase in a cigarette dose-dependent manner across all combinations of genotypes. Furthermore, a 7- to 8-fold variation in risk was found among the various combinations; 3.2 in individuals with combined GSTM1(+) and CYP1A1(m2/m2) and 21.9 in those with combined GSTM1(-) and CYP1A1(m2/m2) genotype when the smoking index (sigma cigarettes smoked per day x years of smoking) was set at > or = 800. The results suggest that individuals having CYP1A1(m2/m2) are relatively resistant to tobacco-related lung cancers when combined with GSTM1(+), but are highly susceptible when combined with GSTM1(-). Combined CYP1A1 and GSTM1 genotype is thus a potential predictor of genetic susceptibility to smoking-related lung cancers in populations where CYP1A1 m2 or Val alleles are common.