BRAF is the most common mutation in papillary thyroid carcinoma (PTC) and can be associated with aggressive disease. Previously, a highly sensitive blood RNA-based BRAF assay was reported. The objective of this study was to assess the correlation of BRAF circulating tumor RNA levels with surgical and medical treatment. Circulating BRAF levels were assessed in (i) a murine model of undifferentiated (anaplastic) thyroid carcinoma with known BRAF mutation undergoing BRAF -inhibitor (BRAFi) treatment, and (ii) in 111 patients enrolled prior to thyroidectomy (n = 86) or treatment of advanced recurrent or metastatic PTC (n = 25). Blood samples were drawn for BRAF analysis before and after treatment. Testing characteristics were assessed and positivity criteria optimized. Changes in blood BRAF values were assessed and compared to clinical characteristics and response to therapy. In a murine model of anaplastic thyroid carcinoma with BRAF mutation, blood BRAF RNA correlated with tumor volume in animals treated with BRAFi. In tissue BRAF -positive (n = 36) patients undergoing initial surgery for PTC, blood BRAF levels declined postoperatively (median 370.0-178.5 fg/ng; p = 0.002). In four patients with metastatic or poorly differentiated thyroid carcinoma receiving targeted therapies, blood BRAF declined following therapy and corresponded with radiographic evidence of partial response or stable disease. This study shows the correlation of blood BRAF levels in response to treatment in both an established animal model of thyroid cancer and in patients with BRAF -positive tumors with all stages of disease. This assay represents an alternative biomarker in patients with positive thyroglobulin antibodies, and tumors, which do not express thyroglobulin.