Thallium-201- (201Tl) chloride is known to accumulate in metastatic foci of differentiated thyroid carcinoma, but small and deep-seated lesions are generally not detectable by planar imaging. We have evaluated the use of 201Tl-chloride single-photon emission computed tomography (SPECT) in 41 post-thyroidectomy patients with differentiated thyroid carcinoma and one with medullary carcinoma; planar imaging alone was done in eight additional patients (total 50). Of 20 patients with known metastatic disease, planar 201Tl images were positive in 12 (60%) but SPECT revealed an additional 5 (25%) who had metastases (total 85%). SPECT revealed foci as small as 1.0 cm in the neck and 1.5 cm in the lungs, and was particularly useful in detection of disseminated micronodular pulmonary metastases, especially in patients whose scans were negative with diagnostic doses of 131I. Some pitfalls in interpretation of the tomographic reconstructions were found. Thallium-201 SPECT is a marked improvement over planar imaging in the detection of metastases of differentiated thyroid cancer.