OBJECTIVE To examine the association between Ser326Cys polymorphism in hOGG1 gene, which is involved in the repair of 8-hydroxyguanine in damaged DNA, and investigate the risk of squamous cell carcinoma of the esophagus in Chinese. METHODS Ser326Cys polymorphism in hOGG1 gene was determined by PCR-SSCP approach among 201 normal controls and 196 patients with squamous cell carcinoma of the esophagus. The association between this genetic polymorphism and the risk of the cancer was examined by a multivariate analysis. RESULTS The Cys/Cys genotype of hOGG1 was found in 21.4% of patients with the cancer and in 13.4% of controls (P<0.05). Homozygosity for the Cys/Cys genotype significantly increased the risk of developing esophageal cancer, with the odds ratio adjusted for age, sex and smoking being 1.9(95% CI 1.3-2.6). Smoking also significantly increased esophageal cancer risk in this case-control study (adjusted OR 2.6; 95% CI 1.7- 3.9). No interaction between smoking and Cys/Cys genotype was observed for the risk of esophageal cancer. CONCLUSIONS Polymorphism of hOGG1 Ser326Cys may play a role in esophageal carcinogenesis.