Context: Telomerase promoter mutations (TERT) were recently described in follicular cell-derived thyroid carcinomas (FCDTC) and seem to be more prevalent in aggressive cancers. Objectives: We aimed to evaluate the frequency of TERT promoter mutations in thyroid lesions and to investigate the prognostic significance of such mutations in a large cohort of patients with differentiated thyroid carcinomas (DTC). Design: Retrospective observational study. Setting and patients: We studied 647 tumors and tumor-like lesions. A total of 469 patients with FCDTC treated and followed in five University Hospitals were included. Mean follow-up (±SD) was 7.8±5.8 years. Main outcome measures: Predictive value of TERT promoter mutations for distant metastasization, disease persistence at the end of follow-up and disease-specific mortality. Results: TERT promoter mutations were found in 7.5% of papillary carcinomas (PTC), 17.1% of follicular carcinomas (FTC), 29.0% of poorly differentiated carcinomas and 33.3% of anaplastic thyroid carcinomas. Patients with TERT-mutated tumors were older (p<0.001) and had larger tumors (p=0.002). In DTC, TERT promoter mutations were significantly associated with distant metastases (p<0.001) and higher stage (p<0.001). Patients with DTC harboring TERT promoter mutations were submitted to more radioiodine treatments (p=0.009) with higher cumulative dose (p=0.004), and to more treatment modalities (p=0.001). At the end of follow-up, patients with TERT-mutated DTC were more prone to have persistent disease (p=0.001). TERT promoter mutations were significantly associated with disease-specific mortality [in the whole FCDTC (p<0.001)] in DTC (p<0.001), in PTC (p=0.001) and in FTC (p<0.001). After adjusting for age at diagnosis and gender, the HR was 10.35 (95%CI 2.01-53.24; p=0.005) in DTC and 23.81 (95%CI 1.36-415.76; p=0.03) in PTC. Conclusions: TERT promoter mutations are an indicator of clinically aggressive tumors, being correlated with worse outcome and disease-specific mortality in DTC. TERT promoter mutations have an independent prognostic value in DTC and, notably, in PTC.