Cytochrome P450 2A6 (CYP2A6) is the principal enzyme involved in the metabolic activation of tobacco-specific nitrosamines to their ultimate carcinogenic forms and metabolism of nicotine. We investigated the effects of the CYP2A6*4, an entire CYP2A6 gene deletion-type polymorphism, on lung cancer risk and daily cigarette consumption in Japanese male smokers via a hospital-based case control study. The frequency of the CYP2A6*4 variant was compared in 370 lung cancer patients and 380 control smokers. A markedly reduced adjusted odds ratio for lung cancer risk, 0.23 [95% confidence interval, 0.08-0.67], was seen in the group with homozygous deletion (*4/*4) when the odds ratio for a group with homozygous wild (*1A/*1A) was defined to be 1.00 by logistic regression. The subjects with lung cancer were additionally divided into three groups according to the histological classification of the cancer and examined for an association with the CYP2A6 polymorphism. The *4/*4 genotype was not found in patients with squamous cell carcinoma (0 of 105) or small cell carcinoma (0 of 44), indicating that subjects with the *4/*4 genotype have low risk for lung cancers, particularly those caused by tobacco smoke. Furthermore, a significant reduction of daily cigarette consumption was observed in smokers with the *4/*4 genotype, suggesting a possibility that complete lack of CYP2A6 appeared to affect the smoking behavior. These data suggest that male smokers possessing the *1A/*1A genotype have higher risk for tobacco-induced lung cancers.