Cadmium and lead are metallic food contaminants of continuing worldwide concern because of their toxicity, exposure, bioaccumulation and wide dispersion in the environment. Cytochrome P450 2A6 (CYP2A6), known also as nicotine C-oxidase and coumarin 7-hydroxylase, is an inducible liver enzyme with a high degree of genetic variability. It oxidizes the tobacco alkaloid nicotine to cotinine and 3′-hydroxycotinine and metabolizes coumarin to its 7-hydroxy derivative. Here, we have quantified the effects of exposure to cadmium and lead on the variation in CYP2A6 activity and likelihood of adoption of smoking habits in relationship to CYP2A6 genotype in a group of 290 normal Thai women and men with mean age of 32 years. Geometric mean for urinary Cd excretion of the group was 0.33 μg/day and the geometric mean for urinary Pb excretion was 0.98 μg/day. The prevalence of smokers was 82% in men having one allele of the *1B or *7 in whom Cd induction of CYP2A6 was more pronounced than those having two *1B alleles with a smoking prevalence of 44%. In the high-risk genotype, Cd body burden alone explained 74% of total variation in CYP2A6 activity. However, in the low-risk genotype, Cd and Pb exposures explained only 48% of the variation in CYP2A6 activity. The weaker CYP2A6 induction by Cd was due to an antagonistic effect of Pb evident from an inverse association between Pb and CYP2A6 activity. Thus, the induction of CYP2A6 by Cd increases the smoking risk by 1.9 fold in men with one allele of the *1B or *7, compared with those having the *1B/*1B genotype. We have thus demonstrated that environmental exposures to, and accumulation of Cd experienced by the subjects in the present study have effects on the expression of the human CYP2A6 gene and on the likelihood of acquiring a smoking habit. These findings show the influence of environmental exposure to cadmium on the expression of the gene involved in nicotine clearance and links this environmental factor with smoking.