Objective The objective of this study is to investigate the risk and prognostic factors for radioactive iodine (RAI)-refractory (RAIR) differentiated thyroid cancer (DTC) with distant metastasis. Methods A total of 128 patients with distant metastasis-DTC who underwent iodine-131 radiotherapy were included in this cohort study. After exclusion, 75 DTC patients who were resistant to radioiodine therapy and 53 patients in whom the treatment was successful were finally included. Clinical data as well as BRAF V600E and telomerase reverse transcriptase (TERT) promoter mutations were compared between these two groups to predict the risk of RAIR. Patients with RAIR-distant metastasis-DTC were followed up to further investigate the risk factors for disease progression after the cancer became iodine-refractory. Results Univariate analysis showed that TERTp mutation, age at diagnosis, mean maximum tumor diameter, lymph node metastasis, synchronous metastasis or heterochronous metastasis, mean cumulative dose of RAI, and preoperative Tg were statistically different between the RAIR and RAIE (radioiodine efficient) groups. Logistic regression analysis further found that the TERTp mutation may be risk factor for iodine refractory occurrence. During the follow-up of RAIR-distant metastasis-DTC patients, 41 patients developed disease progression, and 24 patients had good disease control. Conclusion We found that TERTp mutation is correlated with the poor curative effect of RAI therapy in distant metastasis-DTC. Once iodine refractory occurs, patients aged 55 years or older are more likely to develop disease progression.