Defects in the non-homologous end-joining (NHEJ) DNA repair pathway lead to genomic instability and carcinogenesis. However, the roles of individual NHEJ genes in nasopharyngeal carcinoma (NPC) etiology are not well-understood. The aim of this study was to assess the contribution of NHEJ genotypes, includingXRCC4(rs6869366, rs3734091, rs28360071, rs28360317, rs1805377),XRCC5(rs828907, rs11685387, rs9288518),XRCC6(rs5751129, rs2267437, rs132770, rs132774),XRCC7rs7003908, andLigase4rs1805388, to NPC risk, with 208 NPC patients and 416 controls. Genotype–phenotype correlations were also investigated by measuring mRNA and protein expression in adjacent normal tissues and assessing the NHEJ repair capacity in blood lymphocytes from 43 NPC patients. The results showed significant differences in the distributions of variant genotypes atXRCC4rs3734091, rs28360071, andXRCC6rs2267437 between the cases and controls. The variant genotypes of these three polymorphisms were associated with significantly increased NPC risks. NPC patients with the risk genotypes atXRCC6rs2267437 had significantly reduced expression levels of both mRNA and protein, as well as a lower NHEJ repair capacity, than those with the wild-type genotype. In conclusion,XRCC4rs3734091, rs28360071, andXRCC6rs2267437 in the NHEJ pathway were associated with NPC susceptibility. XRCC6rs2267437can modulate mRNA and protein expression and the NHEJ repair capacity.