An association of oral squamous cell carcinoma (SCC) susceptibility with an MspI restriction site polymorphism of the CYP1A1 gene and GSTM1 polymorphism were reported in our previous study (Sato M, Sato T, Izumo T, Amagasa T. Genetic polymorphism of drug-metabolizing enzymes and susceptiblility to oral cancer. Carcinogenesis 1999;20:1927-31). We report here that genetic risk for oral SCC was associated with another isoleucine-valine (Ile-Val) polymorphism, which resulted in an Ile-Val amino acid replacement in the heme-binding region of CYP1A1, and combined genotyping of CYP1A1 and GSTM1 genes in relation to the cumulative cigarette-smoking dose. The genetic polymorphisms of CYP1A1 and GSTM1 genes in oral cancer susceptibility were assessed by examining polymorphic prevalences in 142 oral SCC patients and 142 healthy controls who were individually matched to the patients with respect to sex and age (+/-1 year). Individuals with a combined genotype of Val/Val and GSTM1(-) were at an increased risk for oral SCC compared with other combined genotypes, in particular, at a low dose level of cigarette smoking.