The human oxoguanine glycosylase 1(hOGG1) gene encodes a DNA glycosylase that is involved in excision repair of 8-OH-dG (8-hydroxy-2-deoxyguanine) from oxidatively-damaged DNA. To determine whether hOGG1 plays a role in the risk for adenocarcinoma of the gallbladder, we tested the association of this polymorphism with gallbladder cancer in a Chinese population-based, case control study of 204 cases and 209 controls. The subjects were genotyped with a polymerase chain reaction-restriction fragment length polymorphism (PCR-RELP) assay. The association between the genetic polymorphism of this gene and risk of the cancer was examined by using a multivariate analysis. We found that the distribution of hOGG1 Ser326Cys genotypes among controls (Ser/Ser, 37.3%; Ser/Cys, 53.6% and Cys/Cys, 9.1%) was significantly different from that among gallbladder cancer cases (Ser/Ser, 43.1%; Ser/Cys, 36.3% and Cys/Cys, 20.6%). Significantly increased risk for gallbladder cancer was both the hOGG1 326Ser/Cys (Odds ratio [OR] = 1.9, 95% confidence interval (CI) = 1.0-3.7) and hOGG1 326Cys/Cys genotypes (OR = 4.5, 95% CI = 1.1-22.4). We observed no statistically significant association between hOGG1 genotype and gallbladder cancer association in gallstone absence. In contrast, a near-significant increase in risk for gallbladder cancer was observed for gallstone presence with the hOGG1 326Ser/Cys genotype (OR = 2.2, CI = 1.4-3.5) whereas a significant increase in association for gallbladder cancer was observed for gallstone presence with the 326Cys/Cys genotype (OR = 6.1, CI = 2.1-27.2). These data corresponded with the fact that a significant trend towards increased association for gallbladder cancer was observed with potentially higher-risk hOGG1 genotypes in gallstone presence(p < 0.001, chi(2) trend test)but not in gallstone absence(p = 0.89, chi(2) trend test). A significant increase in risk for gallbladder cancer was observed for larger gallstone (those with stone diameters 2 cm or greater) with the hOGG1 326Ser/Cys(OR = 1.9, 95% CI = 1.1-2.9) and hOGG1 326Cys/Cys genotypes(OR = 5.9, 95% CI = 1.6-18.0). These data are consistent with the observation that a significant trend towards increased risk for gallbladder cancer was observed with potentially higher-risk hOGG1 genotypes in gallbladder cancer patients with larger gallstone (p < 0.001, chi(2) trend test). However, we observed no statistically significant association between hOGG1 genotype and gallbladder cancer risk in gallbladder cancer patients with smaller gallstone (those with stone diameters 2 cm smaller) (hOGG1 326Ser/Cys:OR = 2.2, 95% CI = 0.8-4.0; hOGG1 326Cys/Cys:OR = 2.9, 95% CI = 0.6-29.4; p = 0.06, chi(2) tread test). These results suggest that hOGG1 Ser326Cys polymorphism is associated with gallbladder cancer risk.