Because of the limitations of periodic 131I whole-body scans, including suspension of substitution therapy, questionable sensitivity and low yield in detecting metastases in patients who have undergone thyroidectomy, serum thyroglobulin and 131I whole-body scans were evaluated for sensitivity in detecting local, regional or distant metastases in 261 patients with differentiated thyroid carcinoma after total thyroidectomy and ablation. METHODS A noncompetitive immunoradiometric assay was used for serum thyroglobulin determination. An 131I whole-body scan was obtained after replacement therapy had been suspended for 6 wk or when TSH reached levels higher than 50 microU/ml. In patients who underwent radiological procedures with iodinated contrast media, the waiting period before the 131I whole-body scan was no less than 10 wk. RESULTS Of the 58 patients with proven metastases who were followed for 12 yr (mean 7 +/- 3.3 yr), 51 (88.4%) had high serum thyroglobulin assays performed while under full replacement therapy and 32 (55%) showed clear 131I whole-body scan localization. There were no instances of positive whole-body scans and negative serum thyroglobulin. CONCLUSIONS In patients treated with 131I, serum thyroglobulin assay was an excellent method to assess treatment. Patients with metastatic disease and negative whole-body scans with or without serum thyroglobulin exhibited a trend toward higher mortality. This trend may also indicate that the lack of 131I trapping and low thyroglobulin is a sign of metabolic dedifferentiation of otherwise histologically differentiated thyroid tumors.