Background Oncogenic BRAF mutations are commonly found in advanced differentiated thyroid cancer, and reports have shown efficacy of BRAF inhibitors in these tumors. We investigated the difference in response between dabrafenib monotherapy and dabrafenib+trametinib therapy in patients with BRAF-mutated radioactive iodine refractory differentiated thyroid cancer. Methods In this open-label randomized phase 2 multicenter trial, patients aged ≥18 years with BRAF-mutated radioactive iodine refractory differentiated thyroid cancer, and with progressive disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 within 13 months prior to enrollment were eligible. Patients were randomly assigned to receive dabrafenib alone, or dabrafenib+trametinib. The primary endpoint was objective response rate by modified RECIST (minor response of -20% to -29%, partial and complete response) within the first 24 weeks of therapy. Trial Registration Number: NCT01723202 Results A total of 53 patients were enrolled. The objective response rate (modified RECIST) was 42% (11/26, 95% CI: 23%-63%) with dabrafenib versus 48% (13/27, 95% CI: 29%-68%) with dabrafenib+trametinib (p=0.67). Objective response rate (RECIST 1.1) was 35% (9/26, 95% CI: 17%-56%) with dabrafenib and 30% (8/27, 95% CI: 14%-51%) with dabrafenib+trametinib. Most common treatment-related adverse events included skin and subcutaneous tissue disorders (17/26, 65%), fever (13/26, 50%), hyperglycemia (12/26, 46%) with dabrafenib alone, and fever (16/27, 59%), nausea, chills, fatigue (14/27, 52% each) with dabrafenib+trametinib. There were no treatment-related deaths. Conclusions Combination dabrafenib+trametinib was not superior in efficacy when compared to dabrafenib monotherapy in patients with BRAF-mutated radioiodine refractory progressive differentiated thyroid cancer.