Metallothioneins (MTs) are cysteine‐rich proteins that act as antioxidants. A case‐control study was conducted to assess the effects of gene polymorphisms in the MT region on the risk of lung cancer in Japanese subjects: 769 lung cancer cases and 939 non‐cancer controls. Associations were evaluated using logistic regression models with adjustment for potential confounders (age, sex, and lifestyle factors including smoking, drinking, and green‐yellow vegetable intake). We found five polymorphisms in the MT‐1 gene region that showed statistically significant associations with lung cancer. Of these polymorphisms, rs7196890 showed the strongest association (odds ratio: 1.30, P = 0.004, 95% confidence interval: 1.09–1.55). The impact of the polymorphism decreased with the increase of smoking, and virtually no association with lung cancer was observed among heavy smokers whose pack‐year values were 30 or more (odds ratio: 1.02, P = 0.93, 95% confidence interval: 0.67–1.55). These results suggest that polymorphisms in the MT gene are moderately associated with the risk of lung cancer and that the associations are modified by lifestyle factors. © 2014 Wiley Periodicals, Inc.