Abstract: Objective Investigate the association between genetic polymorphism of DSBs repair gene XRCC4, RAD51 and susceptibility to esophageal cancer (EC). Methods A hospital based case-control study with 123 EC cases and 61 controls in a Chinese population was conducted. PCR-RFLP was applied to investigate the genotype of XRCC4 promoter G-1394T (rs6869366) and RAD51-G135C and then statistical analysis was conducted by calculating the adjusted odds ratios (OR) and 95% confidence intervals (95%CI). Results A significant difference of XRCC4-1394 polymorphism was observed between EC cases and controls (P<0.05). Carriers of the XRCC4 rs6869366 G allele (GC+GG) were at a higher risk of developing EC with the TT genotype as reference (OR=3.022, 95%CI=1.487-6.142, P=0.002). When GG served as the reference group of RAD51-G135C allele, variant genotype (GC and CC) had a significant increased risk of lung cancer (OR=3.643,95%CI=1.501-8.842,P<0.05). Conclusion Our findings indicated that genetic variants in DNA repair pathways may be involved in esophageal tumorigenesis. XRCC4 G-1394T and RAD51-G135C conferred risk for the process of developing EC.