We reported an association of smoking-induced lung cancer susceptibility with the human cytochrome P450 1A1 (CYP1A1) polymorphisms in our previous studies. To investigate a relationship between genetically determined individual predispositions and mutations of target genes in the early stage of lung carcinogenesis, we examined p53 mutations in relation to germ line polymorphisms of the CYP1A1 and GSTM1 genes, using surgical specimens of 148 non-small cell lung cancer patients who were smokers. The frequency of p53 mutations among heavy smokers was higher than in patients who had never smoked [P < 0.01; odds ratio (OR), 3.74; 95% confidence interval (CI), 1.46-9.56]. By single-strand conformational polymorphism, aberrant migration bands of p53 gene fragments were detected in 56 cases (38%). Smokers with susceptible rare homozygous alleles of either the MspI or Ile-Val polymorphism of the CYP1A1 gene have a 4.5-fold (P < 0.005; OR, 4.48; 95% CI, 1.64-12.26) or 5.5-fold (P < 0.01; OR, 5.52; 95% CI, 1.55-19.64) higher risk of having a mutation of the p53 gene than those with nonsusceptible predominant homozygous alleles of the gene. Non-small cell lung cancer patients with a susceptible CYP1A1 genotype were at remarkably high risk of having a mutation of the p53 gene when the genotype was combined with a deficient genotype, GSTM1(-). However, there was no difference between the types of p53 mutation and genotypes of the drug-metabolizing enzymes. These results showed that CYP1A1 germ line polymorphisms, which were associated with the genetic predisposition for lung cancer, were related to cigarette smoking-associated p53 mutations.