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The overall estimated risk of recurrence after an apparently complete thyroid cancer resection ranges from1% to 55%, and the high-quality pathology report is crucial for proper risk stratification. The neck ultrasound (US) and serum thyroglobulin (Tg) and anti-Tg antibody (TgAb) assays are the mainstays for Differentiated Thyroid Cancer (DTC) follow-up. However, the neck US includes a high frequency of nonspecific findings and despite the serum, Tg unmasks the presence of thyrocytes, it is not discriminating between normal and malignant cells. In this study, to improve post-surgery follow-up of minimal residual disease in papillary thyroid cancer (PTC) patients, blood-derived cytology specimens were evaluated for the presence of circulating tumor cells (CTCs). The presence of CTCs of thyroid origin was confirmed by cytomorphological and tissue-specific antigens analysis (Thyroid Transcription Factor-1/TTF-1 and Tg) and proliferative profile (percentage of cells in S-phase). Our data revealed an unfavorable' prognostic risk in patients with5% CTCs (p = 0.09) and with30% S-phase cells at baseline (p = 0.0015), predicting ≤1 year relapsing lesion event. These results suggest a new intriguing frontier of precision oncology forefront cytology-based liquid biopsy.