Nasopharyngeal carcinoma (NPC) is known for its high metastatic potential. From genomic expression profiles comparing clones derived from the NPC cell line CNE-2, serglycin (SRGN) was identified as one of the most up-regulated genes in the high-metastasis clone. Serglycin protein was secreted by the high-metastasis clone, but not by any of the low-metastasis clones. Suppression of serglycin by shRNA diminished serglycin secretion and subsequently inhibited the migration and invasion of high-metastasis clone, and also reduced its metastasis rate in vivo. Overexpression of serglycin in low-metastasis cells resulted in an increased metastasis rate in vivo. Moreover, secreted serglycin promoted cellular motility in the wild-type low-metastasis cells. Interestingly, suppression of serglycin reduced the protein level of vimentin but did not influence the level of E-cadherin in high-metastasis clone. Proliferation was not influenced by serglycin in both high-and low-metastasis clones. Clinically, serglycin expression was significantly elevated in liver metastases from NPC relative to its expression in primary tumors. The prognostic value of serglycin was evaluated by immunohistochemical staining of tissue microarrays of NPC tissues from 263 patients, followed by multivariate analyses. A high level of serglycin expression in primary NPC was found to be an independent unfavorable indicator for distant-metastasis-free survival and disease-free survival. In summary, serglycin regulates NPC metastasis via autocrine and paracrine means without influencing proliferation, and it serves as a prognostic indicator of metastasis-free survival and disease-free survival for NPC patients.