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Aim: to test the possible association between the polymorphism of Osteopontin (OPN) gene with the risk and the clinical features of papillary thyroid cancer (PTC). Methods: A total of 363 PTC patients and 413 healthy controls were enrolled. OPN expressions in tumor tissue were detected by immunohistochemistry. OPN gene polymorphisms, namely, -66T>G (rs28357094), -156G>GG (rs17524488), and -443C>T (rs11730582), were determined. Results: We observed that the PTC patients had significantly higher rates of -443TT genotypes than controls (PConclusion: This study provides evidence to support the connection between the OPN genetic polymorphism and tissue expression with risk as well as the invasiveness of PTC.