Persistent disease remains a key challenge in differentiated thyroid cancer (DTC), contributing to higher treatment burden. With the updated American Thyroid Association (ATA) 2025 dynamic risk stratification, there is growing interest in whether routine clinical and biochemical parameters differ between patients with and without persistent disease. Identifying such differences may support earlier risk characterization and personalized follow-up strategies.

A retrospective observational study was performed from 1 July to 15 November 2025. All DTC patients admitted for hypothyroid-based RAI therapy were included, except those receiving initial RAI treatment. Disease response categories—structural incomplete, biochemical incomplete, indeterminate, and excellent—were defined using ATA 2025 criteria. Patients were classified into persistent (structural or biochemical incomplete) and non-persistent (indeterminate or excellent). Continuous variables were non-normally distributed and summarized as median (IQR), with comparisons using Mann–Whitney and chi-square tests. A subgroup analysis compared patients with structural incomplete response with and without distant metastasis.

A total of 211 patients met inclusion criteria. No significant differences were found in age, sex, or BMI between persistent and non-persistent disease groups. Significant differences were observed in thyroglobulin (Tg) levels (1.50 [1.50–4.13] vs. 53.26 [11.25–250.00] ng/mL, p = 0.001), cumulative I-131 dose (190 [130–410] vs. 370 [250–630] mCi, p = 0.001), and initial ATA 2025 risk stratification (p = 0.003; 155 patients with available data). In the structural incomplete subgroup (n = 111), patients with distant metastasis were older (49.50 [33.92–57.50] vs. 57.58 [44.67–63.85] years, p = 0.011), had higher Tg levels (42.20 [8.20–225.30] vs. 250.00 [201.15–341.50] ng/mL, p = 0.001), received higher cumulative I-131 doses (330 [250–615] vs. 595 [330–817.50] mCi, p = 0.001), and underwent more RAI treatments (3 [2–5] vs. 4.5 [3–6.75], p = 0.002). No significant difference in initial ATA 2025 risk stratification was found in this subgroup (79 patients with complete data, p = 0.319).

Higher Tg levels and greater cumulative RAI dose were associated with persistent disease, while demographic characteristics were not. Among structural incomplete responders, metastatic disease was linked to older age, elevated Tg, and more intensive RAI therapy—but not to initial ATA 2025 risk stratification. These findings highlight clinical and biochemical differences that may help characterize persistent or metastatic DTC and guide tailored management.