X-ray repair cross complementing 1 (XRCC1) protein plays an important role in base excision repair. Single nucleotide polymorphisms (SNPs) in XRCC1 gene may affect DNA repairing ability and genetic susceptibility to cancer. This study was designed to investigate the correlation of XRCC1 Arg194Trp Arg280His and Arg399Gln SNPs with the risk of gastric cardiac adenocarcinoma (GCA). Genotypes were analyzed by polymerase chain reaction-restriction fragment length polymorphism assay in 455 patients with GCA and 650 age and sex-matched controls. We did not find any significant difference in allele and genotype distributions of Arg194Trp Arg399Gln between the groups (P > 0.05). However, a significant increase in GCA risk was seen among smokers if they carried at least one XRCC1 280His (Arg280His + His280His) genotype (odds ratio = 1.59, 95%confidence interval = 1.01-2.51) compared with smokers not carrying these genotype. Our results indicated that XRCC1 Arg194Trp and Arg399Gln SNPs might not be associated with the risk of GCA. However, smokers with His allele at codon 280 had a significantly increased risk of GCA.