Background: Recently, we reported that the thyroglobulin (Tg) doubling time (DT) was the most potent prognostic factor in patients with papillary thyroid carcinoma (PTC) who underwent total thyroidectomy. Interestingly 16.2% of the study patients had a decrease in Tg levels over time, giving negative values in Tg-DT. These patients had an excellent outcome. However, most of the patients did not receive ablation with radioactive iodine. Therefore, whether the Tg in these patients was derived from persistent disease or residual thyroid tissue could not be concluded. To resolve this question, we measured serum Tg levels in patients with medullary thyroid carcinoma (MTC) who underwent total thyroidectomy using similar surgical techniques for the treatment of PTC. Methods: Twenty-seven consecutive patients with MTC who underwent total thyroidectomy were selected. Of them, five patients with antibodies to Tg were excluded from the study. In the remaining 22 patients, serum Tg levels were measured before and after surgery. None of the patients received radioactive iodine ablation. They were prescribed levothyroxine as a replacement for the lost thyroid function. Results: Serum Tg levels were detectable preoperatively, while postoperative serum Tg levels were lower than the detectable level, 0.5 ng/mL, in all 22 patients. Conclusions: The results indicate that most of the patients with detectable Tg levels and negative Tg-DT values after total thyroidectomy for PTC in our previous study had persistent disease, and that their serum Tg was not from residual thyroid tissue, suggesting that up to 50% of patients with persistent PTC have a decrease in serum Tg levels in response to thyroid-stimulating hormone-suppressive therapy.