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Background: Differentiated thyroid carcinoma (DTC), mainly papillary (PTC), at low risk of recurrence is currently managed with active surveillance strategies or less aggressive surgeries. However, total thyroidectomy with 131I treatment is still performed both if these tumors are diagnosed before or occasionally after surgery. This real-life study aimed to evaluate the rate of biochemical, structural, and functional events in a large series of consecutive DTCs at low risk of recurrence treated by total thyroidectomy, but not with 131I, in a medium–long-term follow-up. Patients and Methods: We evaluated clinical–pathologic data of 383 consecutive patients (2006–2012) with unifocal DTC [T1a/b(s)] at low risk of recurrence, treated with total thyroidectomy but without lymph node dissection and 131I treatment after surgery. We evaluated if structural, biochemical, and functional events were detected during the follow-up. Results: Females accounted for 75.7% of our study group, and the median age was 50 years. The median tumor dimension was 0.4 cm (range 0.1–1.2). Most of the patients had a unifocal T1a tumor (98.9%), and 73.6% had a classic variant of PTC. We divided the patients according to the absence (group A—n = 276) or presence (group B—n = 107) of interfering TgAb at first control after surgery. After a median follow-up of 10 years, no structural events were detected. Sixteen out of three hundred and eighty-three (4.2%) patients developed biochemical events: 12/276 (4.3%) in group A and 4/107 (3.7%) in group B. The median time elapsed from surgery to detecting a biochemical event was 14.5 and 77.5 months in groups A and B, respectively. No patients performed additional treatments and were followed up with an active surveillance strategy. Conclusions: This study confirmed that patients with DTC at low risk of recurrence showed an excellent outcome in a medium long-term follow-up since no structural events were diagnosed. Significant variations in Tg/TgAb were detected in a few cases, all managed with an active surveillance strategy without the need for other treatments. Therefore, a relaxed follow-up with neck ultrasound and Tg/TgAb measurement is enough to early identify those very unusual cases of recurrence. [ABSTRACT FROM AUTHOR]