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Simple Summary: Biochemical incomplete response (BIR) is defined as elevated thyroglobulin or rising thyroglobulin antibodies following treatment without structural evidence of disease at 1–2 years after initial treatment. The long-term outcome of such patients is still poorly characterized, with some progressing to structural disease, while others maintain BIR for decades or revert to non-evidence of disease (NED). In this study, we aimed to identify factors that could predict any of the above possible outcomes. In our cohort of 83 BIR patients with a mean follow-up of 12 years, 41% progressed to structural disease. Of them, 11.8% remained BIR, and 38.2% reverted to NED. Although most patients with differentiated thyroid cancer (DTC) and biochemical incomplete response (BIR) follow a good clinical outcome, progression to structural disease may occur in 8–17% of patients. We aimed to identify factors that could predict the long-term outcomes of BIR patients. To this end, we conducted a retrospective review study of 1049 charts from our Differential Thyroid Cancer registry of patients who were initially treated with total thyroidectomy between 1962 and 2019. BIR was defined as suppressed thyroglobulin (Tg) > 1 ng/mL, stimulated Tg > 10 ng/mL or rising anti-Tg antibodies, who did not have structural evidence of disease, and who were assessed 12–24 months after initial treatment. We found 83 patients (7.9%) matching the definition of BIR. During a mean follow-up of 12 ± 6.6 years, 49 (59%) patients remained in a state of BIR or reverted to no evidence of disease, while 34 (41%) progressed to structural disease. At the last follow-up, three cases (3.6%) were recorded as disease-related death. The American Thyroid Association (ATA) Initial Risk Stratification system and/or AJCC/TNM (8th ed.) staging system at diagnosis predicted the shift from BIR to structural disease, irrespective of their postoperative Tg levels. We conclude that albeit 41% of BIR patients may shift to structural disease, and most have a rather indolent disease. Specific new individual data enable the Response to Therapy reclassification to become a dynamic system to allow for the better management of BIR patients in the long term. [ABSTRACT FROM AUTHOR]