Background: Everolimus is an oral inhibitor of the mammalian target of rapamycin (mTOR). Unpublished work from the Fagin lab shows that mTORC1 is also required for the growth promoting effects of the oncoproteins RET/PTC, RAS and BRAF in rat thyroid PCCL3 cells. Further work shows synergy of mTORC inhibitors with RET kinase inhibitors in medullary thyroid cancer cell lines. Sorafenib is an oral kinase inhibitor with in vitro activity against multiple targets, including RAF, RET, VEGFR1, and VEGFR2 that is compendium approved for the treatment of radioactive iodine-refractory (RAIR) and medullary (MTC) thyroid cancer. Methods: The study was a single institution, two-stage phase II design. Primary objective was response rate initiated on 9/21/2010. Eligible patients (pts) had progressive, RAIR/fluorodeoxyglucose (18-F)-avid, recurrent/metastatic, non-anaplastic, thyroid cancer; RECIST measurable disease; and adequate organ/marrow function. Sorafenib was given at 400 mg orally twice a day and Everolimus at 5 mg orally once daily. 41 patients were enrolled; 36 were eligible for the primary endpoint of response and 3 were evaluable for toxicity only at the data cutoff date of 1/10/13. Seventeen patients are still actively on study. Mutational analyses of tissue is ongoing. Results: Of the 41 eligible pts, demographics: female- 44% (18); median age-61 years (35-79). Grade 4-5 adverse events at least possibly related to drug: grade 4- Alanine Aminotransferase Increase (1 pt): grade 4- Hyperglycemia (1 pt): grade 4-Pancreatitis (1 pt). Histology and response data by partial response, confirmed and unconfirmed, (PR), stable disease (SD) and progression of disease (POD) are in the table below. The median time on treatment is 167 days (range 1 to 797 days) at the cutoff date of 1/10/2013. Conclusions: The combination of sorafenib and everolimus shows promising results, especially in the Hurthle cell and medullary subgroups where data from studies at Ohio State have suggested very poor response to sorafenib alone. Clinical trial information: NCT01141309.