In this multicentric retrospective observational study, we investigated the potential risk factors for radioiodine (RAI) indication and the post-treatment recurrence of intermediate-risk differentiated thyroid cancer (DTC) 1 and 3 years from diagnosis. We included 121 patients who underwent thyroidectomy for intermediate-risk DTC. The 92 patients (76.0%) who underwent RAI treatment had a higher prevalence of extra-thyroid micro-extension (mETE) (p = 0.03), pT3 staging (p = 0.03) and recourse to therapeutic central (p = 0.04) and lateral (p = 0.01) neck dissection, as well as higher numbers (p = 0.02) and greater dimensions (p = 0.01) of lymph node metastases, compared with untreated patients. Relapse was observed in 18.1% and 20.7% of cases 1 and 3 years from diagnosis, respectively, with no significant differences between groups. A lower age at diagnosis (p = 0.03) and higher levels of stimulated thyroglobulin (Tg) (p = 0.04) emerged as the only independent risk factors for tumour relapse at 1 year. Tumour relapse at 3 years was only independently predicted by the presence of tumour relapse at 1 year (p = 0.04). In conclusion, mETE, pT3 and the presence of large, multiple or clinically evident lymph node metastases represent the main indicators for referring patients to RAI treatment. Early recurrence may be considered the most relevant factor when planning further surveillance.