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Objective: This study was to investigate the clinical significance of miR-551b-5p and SETD2 in thyroid cancers (TC) and their effects on the biological function of TC cells. Methods: The expression level of miR-551b-5p and SETD2 in tumor/nontumor tissues and TC cell lines was measured by quantitative real-time polymerase chain reaction (RT-qPCR). Subsequently, the relationship between miR-551b-5p or SETD2 expression and the clinicopathological feature was detected by Chi-square analysis. Kaplan-Meier and multivariate Cox regression analyses were used to assess their prognostic values. Finally, the regulatory effects of miR-551b-5p and SETD2 on the proliferation, migration and invasion ability of TC cells were detected by CCK-8 and Transwell assays. Results: Compared with non-tumor groups, the expression of miR-551b-5p was significantly increased in patients' tissues and TC cell lines, while SETD2 mRNA expression was decreased. Patients with up-regulated miR-551b-5p or downregulated SETD2 mRNA in TC showed more positive lymph node metastasis and advanced TNM stage. High miR-551b-5p expression level and low SETD2 mRNA level were related to poor survival rate. miR-551b-5p and SETD2 might be potential prognostic biomarkers for TC. miR-551b-5p knockdown can inhibit cell proliferation, migration and invasion by targeting SETD2. Conclusion: miR-551b-5p and SETD2 may be valuable prognostic biomarkers and new therapeutic targets for TC.