Nitrosamine consumption and polymorphisms in CYP2E1, the product of which is involved in the activation of nitrosamines into reactive intermediates, have been shown to be associated with nasopharyngeal carcinoma (NPC) risk. Given that reactive intermediates created during nitrosamine metabolism are capable of DNA damage, we further hypothesized that differences between individuals in their ability to repair DNA damage might be important in NPC pathogenesis. To evaluate this hypothesis, this study focused on effects of genetic polymorphisms of DNA repair genes hOGG1 and XRCC1 on the development of NPC. We conducted a case-control study to investigate the genotypes of 334 patients with NPC and 283 healthy community controls matched by sex, age, and residence. The PCR-based RFLP assay was used to identify genetic polymorphisms. After adjustment for sex, age, and ethnicity, the odds ratio (OR) of developing NPC for hOGG1 codon 326 genotypes of Ser/Cys and Cys/Cys compared with the Ser/Ser genotype was 1.6 (95% CI, 1.0-2.6). For XRCC1 codon 280 genotypes of Arg/His and His/His compared with the Arg/Arg genotype, the OR was 0.64 (95% CI, 0.43-0.96). Among subjects with putative high-risk genotypes for both hOGG1 and XRCC1, the OR was 3.0 (95% CI, 1.0-8.8). Furthermore, subjects with putative high-risk genotypes for hOGG1, XRCC1, and CYP2E1 had an OR of disease of 25 (95% CI, 3.5-177). Polymorphisms of the DNA repair genes hOGG1 (codon 326) and XRCC1 (codon 280) are associated with an altered risk of NPC. Carriers of multiple putative high-risk genotypes have the highest risk of developing NPC.