Objective：This study aimed to investigate the prognostic factors affecting the radioiodine refractory-differentiated thyroid cancer（RAIR-DTC）and the predictive index. Methods：Differentiated thyroid cancer（DTC） patients who received total thyroid resection were retrospectively collected，with 131I treatment and follow-up in the First Affiliated Hospital of Nanjing Medical University from January 2009 to December 2017. The clinical characteristics，dynamic risk stratification and prognosis stratification were analyzed. The prognostic factors affecting the RAIR-DTC were explored，and the area under the receiver operating characteristic（ROC）curve and 95% confidence interval（CI），sensitivity and specificity of important intercept points were calculated. Results：①A total of 318 DTCs，272（85.5%）had no distant metastasis，46（14.5%）had distant metastasis；32（10.1%）patients were RAIR，286（89.9%）were non-radioiodine refractory（NRAIR）. Comparing with those of NRAIR patients，age and male proportion of RAIR patients was higher，the longest diameter of thyroid lesions of RAIR patients was larger，and the 131I treatment frequency，the distant metastasis rate，the dynamic risk stratification and prognosis stratification of RAIR patients were higher. There was no significant difference in the incidence of nodular lesions，lesions on the left and right，and multifocal lesions between RAIR and NRAIR patients. ②Binary logistic regression analysis showed that males，131I treatment frequency，cervical lymph node reaction were prognostic factors affecting RAIR-DTC. ③The area under the ROC（AUC）indicated that 131I treatment frequency was a major prognostic factor. When DTC patients receiving ≥3 131I treatment，the AUC of predicting RAIR was 0.861（95%CI 0.817-0.897），the sensitivity was 78.12% and the specificity was 88.85%（P＜0.001）. Conclusion：It is suggested to assess the probability of RAIR in ≥ 55 years DTC patients who received ≥3 131I treatment still with at least 1 metastasis without 131I uptake or progressive disease. Once diagnosed as RAIR，molecular targeted therapy should be taken as soon as possible.