OBJECTIVES: Lenvatinib (Lenvima®) and sorafenib (Nexavar®) are the two most recently FDA-approved drugs for treating radioiodine (RAI)-refractory differentiated thyroid cancer (DTC). Both demonstrated superior progression-free survival over placebo in their respective phase III clinical trials. In this study, we compared the cost-effectiveness of the two treatments and placebo in treating RAI-refractory DTC in the U.S. from a societal perspective. METHODS: A Markov model was developed to estimate the costs and health benefits for treatment of RAI-refractory DTC. Transition probabilities were from two phase-III trials—the SELECT trial comparing lenvatinib to placebo, and the DECISION trial comparing sorafenib to placebo. We used a bi-monthly cycle length for a lifetime time horizon. We adjusted the survival rates based on comparisons of the two placebo groups in two trials. Direct medical costs and utility data were obtained from Redbook, Healthcare Cost and Utilization Project, Medicare Fee Schedule, and published literature. All costs were adjusted to 2015 USD, discounted at 3% annually. One-way probabilistic sensitivity analyses were performed. RESULTS: In the base case, placebo was most costly ($851,256), followed by lenvatinib ($197,374), and sorafenib ($164,371).  Placebo was dominated, being the most costly and least effective treatment. High costs of placebo were driven by costs associated with palliative care. At a willingness-to-pay threshold of $100,000/QALY, lenvatinib was the most cost-effective option at $79,118/QALY gained compared with sorafenib. The treatment decisions were found to be sensitive to the treatment costs of lenvatinib and sorafenib, and the health utility of continuing with lenvatinib. CONCLUSIONS: Given a willingness-to-pay threshold of $100,000/QALY, lenvatinib is the most cost-effective treatment, compared with sorafenib and placebo. This finding supports the National Comprehensive Cancer Network guidelines recommending tyrosine-kinase inhibitors for RAI-refractory DTC. Future research efforts should focus on updating results with real-world data and directly comparing the two treatments.