Though anti-angiogenic agents are the bedrock of treatment for radioiodine-refractory differentiated thyroid carcinoma (RAIR-DTC), novel anti-angiogenic agents with optimized features like greater target binding affinities and more favorable pharmacokinetics profile are needed. This phase II randomized, double-blind, placebo-controlled trial investigated the efficacy and safety of anlotinib, a multikinase inhibitor, for RAIR-DTC.Patients (aged between 18 and 70 years) with pathologically confirmed locally advanced or metastatic RAIR-DTC were enrolled and randomly received 12 mg anlotinib once daily or placebo on day 1 to 14 every 3 weeks. Patients on placebo were allowed to receive open label anlotinib after disease progression. The primary endpoint was progression-free survival. The secondary endpoints included overall survival and safety.Between September 2015 and August 2018, 76 and 37 patients randomly received anlotinib and placebo, respectively. Patients receiving anlotinib had a significantly longer median progression-free survival (40.5 months, 95% CI 28.3-NE vs. placebo 8.4 months, 95% CI, 5.6-13.8; HR 0.21, 95% CI 0.12-0.37, P<0.001), meeting the primary endpoint. Overall survival was still immature, with a trend of benefit with anlotinib (HR 0.57, 95% CI 0.29-1.12). All patients in the anlotinib group experienced adverse events; 8 (10.5%) discontinued treatment due to adverse events.Anlotinib demonstrated promising efficacy and favorable tolerance in the treatment of locally advanced or metastatic RAIR-DTC, supporting further research to establish its role in the treatment of this serious disease.