Thirty-seven patients with Hürthle cell carcinoma of the thyroid gland underwent total thyroidectomy and then technetium-99m sestamibi (2-methoxy-isobutylisonitrile), iodine-131 and thallium-201 whole-body scans. Twenty-two of them had elevated human serum thyroglobulin (HTg) levels. Among these 22 patients, abnormal uptake of 131I was seen in four (18.1%), abnormal uptake of 201Tl chloride in 15 (68.1%), and abnormal 99mTc-sestamibi accumulation in 18 (81.8%). No patients with normal levels had a positive whole-body scan. In comparison with the 131I and 201Tl chloride images, the 99mTc-sestamibi images were of superior quality and detected significantly more (P < 0.05) metastatic lesions of Hürthle cell carcinoma of the thyroid gland in patients with elevated HTg after total thyroidectomy. A mechanism is proposed that may explain these findings.