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Background: The role of osteopontin (OPN) in intrahepatic cholangiocarcinoma (ICC) remains controversial. This study aimed to explore the prognostic value of OPN in patients with ICC undergoing curative resection. Methods: Patients undergoing curative resection from 2005 to 2016 were identified for inclusion in this retrospective study. The expression level of OPN in tumors was measured in each of the 228 patients by immunohistochemistry. Circulating OPN in serum was tested in 124 patients by ELISA. Tumor volume was calculated according to preoperative imaging or operation record. Proliferation assay, wound healing assay, and invasion assay were performed to investigate the biological function. Results: Low expression of OPN in tissue was associated with lymph node metastasis (P=0.009) and shorter overall survival (OS) (P=0.001). A low level of circulating OPN/volume was associated with multiple tumors (P＜0.001), vascular invasion (P=0.027), visceral peritoneal perforation (P=0.001), and lymph node metastasis (P=0.002). It was also able to predict the invasive behavior, lymph node metastasis, and early recurrence with the area under the receiver operating curve (AUC) of being 0.719, 0.708 and 0.622 respectively. Patients with a low level of circulating OPN/volume had shorter OS (P=0.028) and disease-free survival (DFS) (P=0.004) and could benefit from adjuvant chemotherapy (P=0.011). Compared with negative controlled cells, ICC cell lines, which expressed more OPN, showed a decelerated proliferation rate, the weaker ability of migration and invasion, while the opposite was true for the cells expressed less OPN. MMP1, MMP10, and CXCR4 were negatively regulated by OPN. Conclusions: A low level of circulating OPN/volume could indicate aggressive characteristics, along with poor prognosis and efficacy of adjuvant chemotherapy in ICC patients. Over expression of OPN may inhibit phenotypes facilitating ICC metastasis by negatively regulating MMP1, MMP10, and CXCR4.