Individual susceptibility to smoking-related cancers is proposed to partly depend on a genetically determined ability to metabolise tobacco carcinogens. We previously reported on the association between the activity of the xenobiotic-metabolising enzyme CYP2D6 and lung cancer risk in a hospital-based case-control study among French Caucasian smokers. Here we extended the study to address the effect of four gene-inactivating mutations (CYP2D6(*)3, (*)4, (*)5 and (*)16) and the gene duplication of the CYP2D6 gene (CYP2D6(*)2x2 or CYP2D6(*)1x2) on lung cancer risk in the same population (150 patients with primary lung carcinoma of squamous cell or small cell histology and 172 controls). The risk of lung cancer associated with the CYP2D6 poor metaboliser genotype (odds ratio 1.5, 95% confidence interval 0.5-4.3) did not differ from that in the reference category of extensive metaboliser and ultra-rapid metaboliser genotypes combined. Lung cancer risks for the CYP2D6 PM genotype amongst light smokers (tobacco consumption </=20 g/day) or heavy smokers (>20 g/day) were not significantly different. The present findings agree with the discrepancy between the phenotype-based and genotype-based studies indicated by the recent meta-analyses.