Background: Single nucleotide polymorphisms (SNPs) in DNA repair genes may alter gene expression and activity and affect response to cancer treatment and patient survival.The present study was designed to evaluate the utility of XRCC1 Arg399Glu and ERCC1 C8092A SNPs as predictors of response to radiotherapy in patients with locoregional nasopharyngeal carcinoma (NPC) using biopsy specimens obtained before treatment.Materials and methods: The study included 75 consecutive patients with locoregional NPC.XRCC1 Arg399Glu and ERCC1 C8092A SNPs were identified from retrospectively collected paraffin-embedded biopsy specimens via Sanger sequencing.Expression patterns of p53 and pAkt protein were analyzed using immunohistochemistry.The effects of the genetic polymorphisms on progression-free survival (PFS) were analyzed using Cox proportional hazards model, Kaplan-Meier method and the log-rank test.Results: Multivariate analysis showed that the ERCC1 8092 A/A genotype carriers [hazard ratio (HR),1.882;95% confidence interval (CI), 1.031-3.438;p=0.039] and the heavy smokers (>20 pack-years) carrying the XRCC1 Arg/Arg genotype (HR: 2.019;95% CI: 1.010-4.036;p=0.047) are significantly associated with decreased PFS rate in locoregional NPC.Moreover, combined positive expression of p53 and pAkt led to significantly increased PFS in subgroups carrying the XRCC1 Gln allele (HR: 7.057;95% CI: 2.073-24.021;p=0.002) and ERCC1 C allele (HR: 2.568;95% CI: 1.056-6.248;p=0.038).Conclusions: The ERCC1 8092C/A polymorphism is an independent predictor of response to radiotherapy in NPC, while the XRCC1 Arg399Glu mutation combined with smoking status appears to be an effective predictor of PFS.Additionally, our results suggest a possible correlation between these genetic polymorphisms and the effect of p53 protein status on survival.