With an increasing incidence of differentiated thyroid cancer (DTC) diagnosis, questions emerge about the optimal duration of follow-up for detecting recurrent disease and its outcomes. The objective of this retrospective research was to assess the clinical course of differentiated thyroid cancer after radioiodine adjuvant treatment in patients monitored over an extended period. Special attention was paid to the analysis of the time from treatment to recurrence. We also assessed patient outcomes after recurrence. A total of 650 patients with DTC after total/near-total thyroidectomy and adjuvant radioiodine post-recombinant human thyrotropin (post-rhTSH) stimulation were evaluated. All patients were followed up with neck ultrasound, serum thyroid-stimulating hormone (TSH), thyroglobulin (Tg), and antithyroglobulin antibody (anti-Tg) measurements at intervals of 6 to 18 months. Only structural recurrences were considered. They were defined as locoregional recurrence confirmed by biopsy or distant metastases [confirmed by computed tomography (CT) or magnetic resonance imaging (MRI), or abnormal foci on radioiodine scintigraphy or 18F-gluorodeoxyglucose positron emission tomography [18 F] FDG-PET scan], regardless of thyroglobulin (Tg) or anti-Tg levels. The median follow-up was 12 years (5-15.5). Structural recurrence was observed in 47 out of 650 patients (7%). All but 3 locoregional recurrences were suitable for surgery. The median time to structural recurrence was 16 months, with only 9 (1.4%) patients presenting with recurrence after more than 60 months. At the time of the database closure, 601 patients (92%) had an excellent response, including 20 out of 47 (42%) patients with structural recurrence. Eighty-one out of 650 patients had died (12.5%) before the database closure. The median age at the last follow-up of the patients who died was 72 years (range 20-88). A second recurrence was diagnosed in 10 out of 650 patients (1.5%), corresponding to 21% (10 out of 47) of patients who had already experienced a recurrence. The median time from radioiodine (RAI) therapy to the second structural recurrence was 108 months. Structural recurrences in DTC are uncommon, with most patients showing a favourable response to treatment. Improved understanding of recurrence timing may define the duration of patient surveillance at reference centres that can be safely discontinued after 5 years in low- and intermediate-risk groups, as indicated in our study.