Purpose <p>Partial patients with biochemical incomplete response (BIR) after initial therapy for differentiated thyroid cancer (DTC) may progress to structural recurrence during follow-up. For better-individualized care, this study analyzed predictors of structural recurrence in patients with BIR after initial radioactive iodine therapy (RAIT).</p> Methods <p>A retrospective study was conducted on 4,263 patients with DTC who underwent thyroidectomy and initial RAIT between June 2009 and August 2023. Patients with either suppressed thyroglobulin (Sup-Tg) &gt; 1 ng/mL or stimulated Tg (Sti-Tg) &gt; 10 ng/mL and negative anti-Tg antibodies (TgAb &lt; 40 IU/mL) without structural disease were enrolled. Pathological examination or imaging confirmed structural recurrence. Sup-Tg change level [ΔSup-Tg% = (Sup-Tg_3rd - Sup-Tg_2nd)/Sup-Tg_2nd × 100%] and other clinicopathological parameters were used to predict structural recurrence in patients with BIR.</p> Results <p>We enrolled 161 patients with a median follow-up of 6.3 years. Fourteen patients (8.7%) progressed to structural disease, 80 (49.7%) remained in BIR status, and 67 (41.6%) recovered with long-term remission. ΔSup-Tg%≥17.08% displayed high specificity (84.4%) for structural recurrence prediction (AUC = 0.705, <i>p</i> = 0.011). Extrathyroid extension, stage III and ΔSup-Tg% were independent predictors of structural recurrence (OR = 4.568, <i>p</i> = 0.038; OR = 9.594, <i>p</i> = 0.015; and OR = 18.781, <i>p</i> &lt; 0.001, respectively). Kaplan–Meier analysis showed that these factors were associated with structural recurrence-free survival. Cox regression analysis found that patients with stage III and ΔSup-Tg%≥17.08% have a higher risk of recurrence (HR = 4.818, <i>p</i> = 0.015 and HR = 10.173, <i>p</i> &lt; 0.001, respectively).</p> Conclusion <p>Longitudinal monitoring of Tg is essential and Tg change level could be used as a predictor of structural recurrence in patients with BIR.</p>