Context: Cell-free nucleic acids circulating in plasma are considered a promising noninvasive tool for cancer monitoring. BRAFV600E mutation in cell-free DNA (cfDNA) could represent an appropriate marker for papillary thyroid carcinoma (PTC). Objective: Our aim is to investigate the role of BRAFV600E-mutated allele in cfDNA as a marker for the diagnosis and follow-up of PTC. Study Design: BRAFV600E allele was detected and quantified by an allele-specific real-time quantitative PCR assay in plasma from 103 patients affected by nodular goiter. As control populations, we enrolled 49 healthy subjects and 16 patients with non-nodular thyroid diseases. Results: The percentage of circulating BRAFV600E was significantly different between patients and controls and throughout different cytological categories of ultrasound-assisted fine-needle aspiration. Patients with a histopathological diagnosis of PTC showed a higher percentage of circulating BRAFV600E (P = .035) compared to those with benign histology. In 19 patients, a second blood draw, taken 3–6 months after surgery, showed a lower percentage of BRAFV600E in cfDNA than the presurgical sample (P < .001). The diagnostic performance of circulating BRAFV600E was assessed by receiver operating characteristic curve analysis resulting in an area under the curve of 0.797. A cutoff value was chosen corresponding to maximum specificity (65%) and sensitivity (80%). On this basis, we evaluated the predictive value of BRAFV600E in Thy 3 patients with a resulting positive predictive value of 33% and a negative predictive value of 80%. Conclusions: The results of the present study provide encouraging data supporting the possibility to take advantage of circulating BRAFV600E in the management of PTC.