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BACKGROUND The current study aims to explore the expression and diagnostic value of cytokeratin 18 (CK) in patients with papillary thyroid carcinoma (PTC). METHODS Patients diagnosed with thyroid tumor, including 127 cases of PTC and 60 cases of benign tumors and 50 healthy controls were included. Serum CK 18, carcinoembryonic antigen (CEA) and thyroglobulin (Tg) were detected using enzyme-linked immunosorbent assay (ELISA). The diagnostic value of serum CK 18, CEA, and Tg for PTC was analyzed by receiver-operating characteristic (ROC) curve. RESULTS We showed novel data that the level of serum CK 18 was higher in PTC patients than that in controls. Upregulation of serum CK 18 correlated with aggressive clinicopathologic characteristics of PTC, including lymph node metastasis, high ASA risk classification, advanced TNM stage, and larger tumor size. Furthermore, serum CEA and Tg levels of thyroid cancer patients were significantly higher than those of the benign group. More importantly, the AUC-ROC of combined serum CEA, Tg, and CK 18 was higher than that of CEA, Tg, and CK 18 alone, indicating the combination of serum CEA, Tg, and CK 18 significantly improved the diagnostic efficiency in PTC patients. CONCLUSIONS Altogether, combined use of serum CK 18, Tg, and CEA may be a promising biomarker in screening benign and malignant thyroid tumors.