OBJECTIVE This study evaluated the potential of Tc-99m sestamibi whole-body scan (WBMIBI) as an alternative to whole-body I-131 scan (WBI) for the follow-up of patients with differentiated thyroid carcinoma. METHODS We evaluated 99 consecutive patients with differentiated thyroid carcinoma who had total or nearly total thyroidectomy followed by an ablative dose of I-131 (86 women, 13 men; mean age, 44 +/- 12 years). WBMIBI was performed and serum thyroglobulin (TG) levels were obtained at least 6 months after I-131 treatment. All persons were receiving levothyroxine therapy. RESULTS From the total of 110 studies performed, WBMIBI and TG were in agreement in 96% and discordant in 4%. From the 27 crossed studies (WBMIBI x TG) with at least one abnormal result, 16 were compared with WBI. In four cases, the WBI did not reveal functioning thyroid tissue when both TG and WBMIBI indicated tumoral activity. In one case of pulmonary metastasis confirmed by chest radiographs, with a normal TG value, the results of both WBMIBI and WBI were positive. CONCLUSIONS WBMIBI should be considered as a scintigraphic method in the follow-up of differentiated thyroid carcinoma. This technique can show the sites of tumoral activity with optimal image resolution, particularly in those with abnormal TG and negative WBI results, and it is a potentially valuable tool in patients with anti-TG antibodies. The WBI in patients having ablation should be reserved only for therapy planning.