OBJECTIVES: The objective of this study was to estimate the Incremental Cost Effectiveness Ratio (ICER) of utilizing lenvatinib for Radioactive Iodine Refractory Differentiated Thyroid Cancer (RR-DTC) in US. METHODS: Lenvatinib is indicated in the US for treatment of patients with RR-DTC who may or may not have received other Tyrosine Kinase Inhibitors (TKI’s) for the management of the disease. An economic model was developed to evaluate the cost effectiveness of lenvatinib against sorafenib – another TKI with a similar indication. Data on progression free survival (PFS) and overall survival (OS) derived from the clinical trials for lenvatinib (SELECT) and sorafenib (DECISION); not from a head to head trial. Health state utility was obtained through a vignette study. A ten year partitioned survival model was developed to estimate the expected outcomes and costs of lenvatinib vs. sorafenib. Frequencies of adverse events were obtained from the respective clinical trials. Data on utilization of direct medical resources was obtained from a chart study conducted on US patients with RR-DTC. Costs incorporated in the model included drug and administration, adverse event treatment, medical costs for hospitalizations, physician visits, end of life and palliative care; the costs were derived from several databases, e.g., OptumInsight, AHRQ, CMS, and Cancer Mpact. RESULTS: Incremental life years (LYs) and quality adjusted life years (QALYs) gained by patients on lenvatinib vs. sorafenib was 0.58 and 0.55 respectively. At a cost for lenvatinib of $438 per day, and sorafenib of $411 per day, the ICER per LY is $98,172 and $103,925 per QALY. Sensitivity analysis results were also consistent with the basecase findings. CONCLUSIONS: With a threshold of $150,000 per QALY, lenvatinib was found to be cost-effective for the indicated population. Given the limited number of therapeutic options available to the patients with RR-DTC, lenvatinib offers a cost effective option for treatment.