The role of thallium-201 (201TI) scintigraphy in the follow-up evaluation of differentiated thyroid carcinoma (DTC) is controversial. Desirable characteristics of 201TI scintigraphy including the potential for no thyroid hormone withdrawal, immediate imaging postinjection, and low radiation burden relative to iodine-131 (131I) suggests it is logistically superior to 131I scintigraphy. Fifty-two patients with DTC were evaluated with 201TI and 131I neck and chest images, and serum thyroglobulin measurements. In post-thyroidectomy and pre-131I ablation therapy patients, very little 201TI accumulation was noted within the thyroid bed, with discordantly increased 131I activity and normal serum thyroglobulin measurements. Twenty-nine percent of patients evaluated after 131I ablative therapy had elevated serum thyroglobulin levels and localized neck and chest abnormalities on 201TI scan that were not seen on 131I studies. Our data suggest that 201TI is more sensitive than 131I diagnostic (5 mCi) studies for detection of DTC, while 131I is more sensitive in detecting normal residual thyroid tissue postoperatively.