We found that even after accounting for both self-reported smoking history (CPD and duration) and internal smoking dose (TNE), and other potential confounders, a one natural log-unit increase in the CYP2A6 enzymatic activity ratio (urinary total 3-HCOT/cotinine) was associated with a statistically significant 46% increased lung cancer risk. This evidence concerns the gene CYP2A6 and lung cancer.