Lenvatinib (Lenvima®) and sorafenib (Nexavar®) are the two most recently Food and Drug Administration-approved drugs for treating radioiodine-refractory differentiated thyroid cancer (RR-DTC). Both demonstrated superior progression-free survival over placebo in their respective Phase III clinical trials. This study compared the cost-effectiveness of the two treatments with placebo from a limited societal perspective.A Markov model was developed to estimate the costs and health benefits for treatment of RR-DTC. The probabilities and survival rates were obtained from two Phase III trials: the SELECT trial comparing lenvatinib to placebo, and the DECISION trial comparing sorafenib to placebo. A bimonthly cycle length and half-cycle correction were used for a lifetime time horizon. Medical costs and utility data were obtained from RedBook, Healthcare Cost and Utilization Project, and the published literature. All costs were adjusted to US$2015, discounted at 3% annually. Then second-order Monte Carlo simulation with distributions was conducted to obtain the acceptability curve to address the uncertainty around model inputs.In the base case, lenvatinib was the most cost-effective treatment compared to sorafenib (incremental cost-effectiveness ratio [ICER] = $25,275/quality-adjusted life year [QALY]) and placebo (ICER = $40,869). Sorafenib is also cost-effective compared to placebo (ICER = $64,067/QALY). The treatment decisions were found to be sensitive to the treatment costs and the health utility associated with lenvatinib and its side effects. The acceptability curve showed lenvatinib optimal 80% of time at WTP of $100,000/QALY.This study suggests that lenvatinib is the optimally cost-effective treatment for RR-DTC, although both lenvatinib and sorafenib are cost-effective compared to placebo.