Background: Everolimus is an oral inhibitor of the mammalian target of rapamycin complex 1 (mTORC1). Laboratory data suggests that mTORC1 activity is required for the growth promoting effects of the oncoproteins RET/PTC, RAS, and BRAF in rat thyroid PCCL3 cells. Sorafenib, an oral kinase inhibitor with activity against multiple targets, is FDA-approved for the treatment of radioactive iodine-refractory (RAIR) thyroid cancer. We conducted a clinical trial evaluating everolimus plus sorafenib for RAIR follicular cell derived thyroid cancers (DTC) and medullary thyroid cancers (MTC). Methods: This single institution study used a two-stage phase II design and was initiated on 9/21/10. Primary objective was response rate. Eligible patients (pts) had progressive, RAIR/fluorodeoxyglucose (18-F)-avid, recurrent/metastatic, non-anaplastic, thyroid cancer; RECIST measurable disease. Sorafenib was given at 400 mg orally twice a day and everolimus at 5 mg orally once daily. 41 pts were enrolled; 38 were eligible for the primary endpoint of response and 3 were evaluable for toxicity only at the data cutoff date of 1/21/15. 7 pts are still on study. Results: Of the 41 eligible pts, median age-61 years (35-79). 15 patients received prior VEGF-targeted systemic therapy. Grade 4-5 adverse events at least possibly related to drug: grade 4- hepatic enzyme increase (1 pt): grade 4- Hyperglycemia (1 pt): grade 4-Hypertriglyceridemia (1 pt). Histology and response data by partial response, confirmed and unconfirmed, (PR), stable disease (SD), progression of disease (POD), and days on study (DOS) are shown in the Table. Conclusions: The combination of sorafenib and everolimus demonstrates activity that rivals the best reported data, and surpasses that for sorafenib alone, in all evaluated thyroid cancer subgroups. A randomized study of sorafenib +/- everolimus is indicated in both pts with DTC and MTC. Clinical trial information: NCT01141309