Liquid biopsies are a minimally invasive approach to obtain biomarkers including cell free DNA (cfDNA) from peripheral blood. Our study evaluated the utility of cfDNA in advanced thyroid cancers. Patients aged >18 years with metastatic medullary thyroid cancer (MTC), poorly differentiated thyroid cancer (PDTC), or anaplastic thyroid cancer (ATC) were enrolled in this prospective study between 2020 and 2024. As part of standard care, sequencing of germline and tumoral DNA was conducted, and patients with germline mutations were excluded from the study. Whole blood samples were collected in Streck cell-free DNA BCT tubes, cfDNA was extracted from plasma using the EZ1and2 ccfDNA kit and EZ2 Connect. The extracted cfDNA was then sequenced across 50 key cancer-related genes using the Oncomine Precision Assay (OPA) panel on an Ion Torrent Genexus Integrated Sequencer. Forty patients were included; 27 MTC, 2 ATC and 11 PDTC. Tumoral mutations were detected in 36 of the included patients (90%): cfDNA detected mutations in 18/36 patients (13 MTC, 1 ATC, 4 PDTC (50%). Sensitivity of cfDNA was 86% (6/7) pre TKI therapy, and reduced to 54% on therapy (13/24), suggestive of lack of tumor-derived DNA shedding with strong on-target treatment efficacy. Median cfDNA concentration was higher in samples with a detected mutation than those without, 11.91 ng/ml vs 5.81 ng/ml respectively. While an increasing cfDNA was associated with worse progression free survival (p < 0.01). cfDNA is a novel biomarker with potential to monitor disease progression in patients with advanced thyroid cancers.