Oxidative stress may be one mechanism by which tobacco smoke causes lung cancer. A common oxidative damage to DNA is the highly mutagenic 7,8-dihydro-8-oxoguanine adduct, which can be repaired by 8-oxoguanine glycosylase I (OGG1). A Ser326Cys substitution polymorphism in the hOGG1 gene has been suggested, based on in vitro data, to reduce the activity of the enzyme. We tested the association of this polymorphism with lung cancer in a population-based, case control study of 298 cases and 405 controls of Caucasian, Japanese, or Native Hawaiian ancestry in Hawaii. Subjects were genotyped with a PCR-RFLP assay, and odds ratios were estimated by logistic regression after adjustment for other observed risk factors, including smoking and vegetable intake. We found marked differences in the frequencies of the hOGG1 Cys variant allele among ethnic groups (45% in Hawaiians, 42% in Japanese, and 22% in Caucasians). The homozygous Cys/Cys genotype was also found to be more common in cases than controls (P = 0.008), with an odds ratio of 2.1 (95% confidence interval: 1.2-3.7) for this genotype compared with the Ser/Ser genotype. Heterozygous individuals were not at increased risk. This association with the Cys/Cys genotype was observed for each sex, ethnic group, and lung cancer cell type. There was also the suggestion that vegetable intake may not be protective against lung cancer among subjects with the Cys/Cys genotype. These data suggest that the presence of two hOGG1 326Cys alleles confers a 2-fold increased risk of lung cancer. Additional studies need to be conducted to confirm this association.