Primary treatment of differentiated thyroid carcinoma consists of total thyroidectomy followed by ablation of thyroid tissue remnants and possible metastases by means of radioactive iodine. After complete destruction of remnants, metastases or recurrence can be detected by measurement of the serum thyroglobulin level as well as by radionuclide methods. Here we report on the sensitivity of diagnostic 123I scintigraphy and serum thyroglobulin measurement for tumour detection in patients with proven recurrence or metastases. Fifty-five patients who received their first high activity (1,850-5,550 MBq) of 123I therapy after total thyroidectomy and 131I ablation were included in the study. The thyroglobulin level was measured both during TSH-suppressive L-thyroxine therapy (Tg-on) and 4-6 weeks after L-thyroxine withdrawal (Tg-off, TSH>20 mU/l). Prior to treatment, whole-body scanning (WBS) was performed 24 h after the administration of 111-370 MBq 123I. The therapeutic activity of 1,850-5,550 MBq 131I was administered within 24 h after diagnostic scanning. The mean interval between 131I therapy and post-therapeutic WBS was 8.6 days (range 3-15 days). The sensitivity of WBS, Tg-on and Tg-off was 75%, 82% and 98%, respectively. The overall sensitivity of the combination of Tg-on with WBS and of Tg-off with WBS was 95% and 100%, respectively. In 12 out of 51 cases either Tg-off or Tg-on or both Tg-on and Tg-off levels were elevated while 123I-WBS was negative. More lesions were visible on the post-therapeutic 131I scan than on the corresponding diagnostic 123I scan (n=13). Tg values increased significantly (P<0.0001) after thyroid hormone withdrawal. Early treatment of distant metastases or tumour remnants of differentiated thyroid carcinoma is favoured and 131I treatment should also be considered in patients with a negative WBS but positive serum Tg level. The finding of a positive Tg-off level, which is clearly above the corresponding Tg-on value, is sufficient to make this decision. Additional diagnostic 123I WBS will not improve sensitivity.