Background: Nasopharyngeal Carcinoma (NPC) is one of the highest mortal malignancies around the world, and its etiology involves a number of sophisticated biological processes.DNA repair related pathways are widely recognized as essential components in the etiology of NPC, yet few studies have systematically evaluated their importance.In this study, we proposed to use a two-stage association analysis for systematically assessing the relevance of DNA repair pathways with NPC.Methods: 755 NPC cases and 755 controls of Cantonese population were recruited by Sun Yat-Sen University Cancer Center (SYSUCC).A total of 676 SNPs for 88 genes belonging to seven DNA repair related pathways were genotyped.After preprocessing the data based on Hardy-Weinberg equilibrium test, minor allele frequency and missing rate, 587 SNPs were remained for subsequent analysis.To avoid missing genes with moderate to small effects, we applied a two-stage approach that combines Fishers combination test and hypergeometric test to summarize the gene-and pathway-level association signals, respectively.Results: In the first stage, 24 DNA repair related genes were identified associated with NPC (α=0.05), of which 17 genes were missed by the traditional single-SNP association analysis.In the second stage, we found that two DNA repair pathways, Nucleotide Excision Repair (NER: P=0.0026) and Mismatch Repair (MMR, P=0.0068) are significantly associated with NPC, in which association between MMR and NPC has not been reported previously.Conclusions: Our study demonstrates that the proposed two-stage approach, geneand pathway-level analysis, is able to capture genes with moderate to small effect, hence increasing the power to identify disease-relevant pathways .