Human 8-oxoguanine DNA N-glycosylase 1 (hOGG1) plays an important role in repairing oxidative DNA damage induced by tobacco carcinogens. In this case-control study, the authors examined the interactive effect of hOGG1 gene polymorphisms and cigarette smoking on the risk of lung cancer in Taiwan. A total of 1,096 cases and 1,007 controls were enrolled from 6 medical centers in Taiwan during 2002-2004. hOGG1 Ser326Cys genetic polymorphisms were determined using the MassARRAY system (SEQUENOM, Inc., San Diego, California). Tobacco smoking history was obtained through personal interview according to a structured questionnaire. Logistic regression analysis was used to estimate multivariate-adjusted odds ratios and 95% confidence intervals. The odds of developing lung cancer for persons with the Cys/Cys genotype versus the Ser/Ser genotype were 1.11 (95% confidence interval (CI): 0.74, 1.65) for never smokers, 1.45 (95% CI: 0.74, 2.83) for moderate smokers, and 3.52 (95% CI: 1.54, 8.06) for heavy smokers. The P value for interaction in the logistic model was 0.01. The increased risk associated with the Cys/Cys genotype among heavy smokers remained statistically significant for various histologic types of lung cancer, including adenocarcinoma, squamous cell carcinoma, and small cell carcinoma. The authors conclude that there was a noticeable modifying effect on the association between hOGG1 genotype and lung cancer risk by cigarette smoking status.