Recently, technetium-99m methoxyisobutylisonitrile (99mTc-MIBI) has been used to image thyroid carcinoma. A prospective study was performed to compare the efficacy of 99mTc-MIBI to thallium-201 (201Tl) scintigraphy in patients with differentiated thyroid carcinoma. The clinical utility of all radionuclide imaging modalities, i.e., 99mTc-MIBI, 201Tl, and iodine-131 Na (131I-Na), as well as serum thyroglobulin estimation, was evaluated. Thirty-four post-thyroidectomy patients (age range: 26-76 years) underwent 45 studies. Histopathologies studied included fourteen papillary, eight papillary-follicular, ten follicular, one Hürthle cell, and one medullary carcinoma of the thyroid. Following optimal stimulation of endogenous thyroid stimulating hormone (i.e, TSH 50 mU/ml), the patients underwent 201Tl and 99mTc-MIBI scintigraphy. Concomitant 131I-Na scintigraphy was performed and serum thyroglobulin levels were measured. Sixteen scan sets were performed prior to 131I-Na ablation therapy. Twenty-nine scan sets were performed following 131I-Na ablation therapy. The presence or absence of thyroid cancer was established by clinical, biochemical, radiologic, and/or biopsy findings. There was no significant difference in sensitivity and specificity of 201Tl scintigraphy versus 99mTc-MIBI scintigraphy in pre- and postablation studies. 131I-Na scintigraphy with determination of thyroglobulin level was sufficient in preablation studies. Among postablation patients, the addition of 99mTc-MIBI or 201Tl offered a higher diagnostic yield. Between the 201Tl and 99mTc-MIBI studies, there was a concordance of 69% in preablation and 97% among postablation patients (P=0.027). It is concluded that 99mTc-MIBI is a suitable alternative to 201Tl scintigraphy in thyroid carcinoma, especially following thyroidectomy and 131I-Na therapy. 131I-Na scintigraphy with serum thyroglobulin is adequate in both pre- and postablation patients. Among the post-131I-Na ablation patients, 99mTc-MIBI or 201Tl is extremely valuable for tumor localization, especially when the 131I-Na whole-body scan is negative. The combination of 99mTc-MIBI or 201Tl scintigraphy with 131I-Na and serum thyroglobulin offers the highest diagnostic yield.