The distribution of cytochrome P450 2E1 (CYP2E1) genetic polymorphism was compared in 126 patients with non-small cell lung cancer (NSCLC) and 612 control subjects by PCR-based assay. Incidence of C type (c2/c2) of CYP2E1 polymorphism in the patients with squamous cell carcinoma (9.4%) was significantly higher than that in healthy controls (4.1%) or in the patients with adenocarcinoma (2.7%) within the Japanese population. The relative risk (95% confidence limit) of C type compared with A and B type in patients with squamous cell carcinoma was 2.45 (0.92-6.48). The incidence of p53 gene mutation was studied in an association with CYP2E1 polymorphism. When all the NSCLC patients were considered, the incidence of p53 mutations in type C (85.7%) was significantly higher than that of A and B type (32.8%). It is suggested that C type of CYP2E1 may define individuals at an increased risk of squamous cell carcinoma through the impaired metabolism of a certain carcinogen which predisposes to p53 gene mutation.