Radioactive iodine (131I) plays a major role in the diagnosis and management of differentiated thyroid cancer (DTC); however, data on the use of the 123I isotope in DTC are limited. We compared 238 diagnostic whole body scans performed 24 h after oral ingestion of 185-555 MBq 123I with their corresponding 131I posttherapy whole body scans obtained 4-5 d after 131I therapy. We studied scans in 3 clinical situations: with the first 131I therapy, with the second 131I therapy, and in cases of elevated Tg and negative diagnostic scan. One hundred and seventy-seven pairs were obtained with the first 131I therapy and showed complete concordance between pretreatment and posttreatment scans in 166 pairs (concordance rate, 93.8%). Six other posttreatment scans showed more foci in the thyroid bed than the pretreatment scans, but no evidence of uptake in new areas. Only 5 posttreatment scans showed foci in new locations: 3 in cervical lymph nodes (CLN), 1 in the lung, and 1 new bone metastasis in a patient with known skeletal metastases. With the second 131I therapy, 34 pairs were obtained and showed complete concordance in 28 pairs (concordance rate, 82.4%). Five discordant pairs showed additional foci in areas that were already positive on pretreatment scans. Only 1 posttreatment scan showed a new bone metastasis in a different site from the bone metastases that were seen on its corresponding pretreatment scan. Of 27 pairs of scans in patients with elevated Tg and negative pretreatment scans, 15 posttreatment scans remained negative, 6 posttreatment scans showed an uptake in the thyroid bed, and 3 other posttreatment scans showed lung uptake in patients whose computed tomography scans of the chest showed only bronchiectasis (in 2 patients) and lung scarring (in the third patient) without evidence of lung metastases. Three posttreatment scans showed definite uptake (in thyroid bed, thyroid bed and lung, and CLN) compared with their corresponding pretreatment scans, which were initially reported negative but were retrospectively thought to have had faint uptake. In 56 pretreatment scans, the 123I diagnostic activity was 185 MBq, and the results showed complete concordance in 54 pairs. Two posttreatment scans showed additional uptake: 1 in the bone and 1 in CLN. These data suggest that pretreatment scanning using 123I is highly comparable to 131I posttreatment scanning and that 123I is an excellent diagnostic agent in DTC.