To investigate the prognostic role of major matrix metalloproteinase (MMP) gene polymorphisms in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) treated with chemoradiotherapy. Four hundred twenty-one consecutive NPC patients were prospectively recruited. Two hundred patients were randomly selected as the training cohort, and the remaining 221 patients were the validation cohort. Twelve polymorphisms in the MMP-1, 2, 3, 7, 8, and 9 genes were genotyped by ligase detection reaction-PCR. MMP-9 rs2250889 PR/RR (HR = 2.287, 95% CI 1.400-3.735) and rs17576 RQ/QQ (HR = 2.347, 95% CI 1.431-3.849) genotypes were significantly related with increased death risk in the training cohort. Analysis of the validation cohort confirmed these results (rs2250889: HR = 2.231, 95% CI 1.281-3.886; rs17576: HR = 2.987, 95% CI 1.674-5.330). Multivariate analysis showed that rs17576 (HR = 2.284, 95% CI 1.123-4.643, P = 0.023) was still an independent prognostic factor. The MMP-9 rs17576 is a novel independent prognostic marker in patients with locoregionally advanced NPC treated with chemoradiotherapy.