Objective: To explore the relationship between TERT promoter mutations and BRAF V600E as well as their coexistence with the clinicopathological features of papillary thyroid cancer (PTC). Methods: A total of 728 patients enrolled in Shanxi Cancer Hospital from December 2014 to December 2016 with PTC were retrospectively analyzed. We reviewed and analyzed the clinical results, pathology records, ultrasound results, and BRAF V600E and TERT status. Results: BRAF V600E mutations were found in 42.3% (308 of 728) of patients, and TERT C228T and C250T promoter mutations were found in 10.7% (78 of 728) and 0.5% (4 of 728) of patients, respectively. The TERT promoter mutation was significantly associated with old age (P=0.034), extrathyroidal invasion (P=0.026), large tumor size (P=0.028), cervical lymph node metastasis (P=0.012), distant metastasis (P=0.001), advanced disease stages (P<0.001), histological type (P=0.003) and recurrence (P=0.002). The BRAF V600E mutation was significantly associated with extrathyroidal invasion (P= 0.001), large tumor size (P<0.001), Hashimoto thyroiditis (P<0.001), distant metastasis (P=0.010), advanced disease stages (P=0.009) and recurrence (P=0.001). The coexistence of BRAF V600E and TERT promoter mutations was particularly associated with high-risk clinicopathological features, such as old age (P=0.024), extrathyroidal invasion (P=0.022), Hashimoto thyroiditis (P=0.005), the cervical lymph node (P=0.018), and advanced disease stages (P=0.002). Conclusions: Our study demonstrates that BRAF V600E and TERT promoter mutations play a significant role in the aggressiveness of PTC, particularly when the two mutations coexist. The results reveal the significant role of these mutations in the treatment and prognosis prediction of PTC.