Background: The thyrotropin (TSH) level or duration of thyroid hormone withdrawal (THW) required to detect stimulated thyroglobulin (Tg) in differentiated thyroid cancer (DTC) monitoring is unknown. The objective of this study was to evaluate the TSH cutoff of > 30 lU/mL as a means to detect stimulated Tg ‡ 2 ng/mL after THW (THW-Tg ‡ 2), and sensitivity of the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) questionnaire for detecting hypothyroid symptoms. Methods: This was a prospective longitudinal cohort study done at a tertiary academic medical center. Fortyseven patients with DTC undergoing their first Tg stimulation or after previously abnormal Tg stimulation had weekly measurements of TSH and Tg during the 4 weeks THW, and repeated questionnaire assessments. Results: TSH did not reach a plateau in any patient, and in those whose Tg did not remain undetectable, Tg continued to rise. Seventy-five percent of patients had an undetectable Tg < 0.2 ng/mL at baseline (95% were < 0.5 mg/mL) with 16% remaining undetectable throughout THW. The majority of patients (72.7% and 97.8%) achieved TSH > 30 lU/mL by 3 and 4 weeks THW, respectively. Of the 15 patients with maximum stimulated THW-Tg ‡ 2, 38% were detected before the minimal TSH > 30 lU/mL cutoff. At 2 weeks THW, 3 had a TSH > 30 lU/mL, and none of them had Tg ‡ 2 ng/mL. At 3 weeks THW, 11 had a TSH > 30 lU/mL, and 64% of them had Tg ‡ 2 ng/mL. Only 60% were detected at 3-week THW regardless of their TSH level. Eighty-six percent were detected by TSH 60-< 80 lU/mL. Conversely, all patients whose serum Tg was < 0.2 ng/mL when their serum TSH was > 20 lU/mL did not achieve a THW-Tg ‡ 2. Conclusion: The minimal TSH cutoff of > 30 lU/mL was inadequate to detect many patients with final stimulated THW-Tg ‡ 2 during complete THW. TSH > 80-100 lU/mL was a better cutoff, achieved in only 53% after 4-week THW. Conversely, we propose a preliminary THW-stopping rule for ending THW early in selected patients. In patients with a Tg < 0.2 ng/mL when TSH > 20 lU/mL, all had a final stimulated Tg £ 2 ng/mL, potentially saving qualifying patients 40% of THW duration compared to 4-week THW. FACIT-F correlated with TSH, but was not sensitive to detect mild hypothyroidism.