Oxidative DNA damage caused by reactive oxygen species plays an important role in cancer development. Human 8-oxoguanine DNA glycosylase (hOGG1) is involved in base excision repair of 8-oxoguanine from damaged DNA. We hypothesized that variants in the hOGG1 gene are associated with risk of renal cell carcinoma (RCC). In a hospital-based case-control study of 572 RCC patients and 575 cancer-free controls frequency matched by age and sex, we genotyped the functional polymorphism Ser326Cys (rs1052133) and assessed its associations with risk of RCC in a Chinese population. We found that individuals with the Cys allele were associated with an increased risk of RCC (odds ratio [OR] = 1.40, 95% confidence interval [CI] = 1.02-1.90), compared with those with the Ser/Ser genotype, particularly among subgroups of body mass index >24 kg/m(2) (OR = 1.75, 95% CI = 1.12-2.73) and non-smokers (OR = 1.60, 95% CI = 1.07-2.38). Further, the polymorphism was associated with risk of developing localized stage and well-differentiated RCC. Our results suggested that the polymorphism is involved in the etiology of RCC and thus may be a marker for genetic susceptibility to RCC.