Objective To study the polymorphism of XRCC1 gene and its relation with genetic susceptibility of the nasopharyngeal carcinoma (NPC) in Chinese living in Jiangsu, Zhejiang Province and Shanghai. Methods A case-control study was performed with 87 NPC patients and 94 healthy controls of Han nationality in Chinese living in Jiangsu, Zhejiang Province and Shanghai. The two groups were matched by sex and age. PCR-RFLP technique was used to explore the relation of different XRCC1 polymorphisms with the susceptibility of NPC. Results The frequencies of the genotypes of XRCC1 Arg194Trp and Arg399Gln were similar between NPC and control groups. The risk of NPC individuals with the Trp194Trp genotype was reduced compared with that in those with Arg194Arg genotype, but with no significant differences (OR=0.41, 95% CI:0.08-1.65, P=0.21). No association was observed between the genetic susceptibility of NPC and other Arg194Trp variants or all Arg399Gln variants. Conclusion Our findings suggest that the polymorphism of XRCC1 has no association with the risk of nasopharyngeal carcinoma in Chinese living in Jiangsu, Zhejiang Province and Shanghai, but the Trp194Trp variant genotype may be associated with a reduced risk of NPC.