Detectable serum Tg levels associated with negative diagnostic (131)I whole body scan are not infrequently found in patients with differentiated thyroid cancer. Several researchers have shown that in these patients the administration of high (131)I activity (100 mCi or more) increases the sensitivity of a posttherapy diagnostic (131)I whole body scan performed a few days later and allows the detection of neoplastic foci not seen with diagnostic doses of (131)I. Empirical radioiodine treatment has also been advocated by some researchers, but its therapeutic effect is controversial. In our institute, positive serum Tg/negative diagnostic (131)I whole body scan patients were not treated with high (131)I activities before 1984; afterward, almost all patients with positive serum Tg/negative diagnostic (131)I whole body scan patients were treated with radioiodine, and a posttherapy diagnostic (131)I whole body scan was performed. In the present retrospective study we compared the outcome of these two groups of patients, 42 treated and 28 untreated, followed for mean periods of 6.7 +/- 3.8 and 11.9 +/- 4.4 yr, respectively. In the treated group the first posttherapy diagnostic (131)I whole body scan was negative in 12 patients and positive in 30 patients. (131)I treatment was further administered only in the latter group. At the end of follow-up in treated patients a complete remission (normalization of serum Tg off L-thyroxine and negative diagnostic (131)I whole body scan) was observed in 10 patients (33.3%). In 9 cases (30%) posttherapy diagnostic (131)I whole body scan became negative, and serum Tg was reduced but still detectable; in 11 patients (36.6%) serum Tg was detectable, and posttherapy diagnostic (131)I whole body scan was positive. The resolution of (131)I uptake in lung metastases was observed in 8 of 9 cases (88.8%) and in cervical node metastases in 11 of 18 cases (61.1%). In patients treated only once because the posttherapy diagnostic (131)I whole body scan was negative (n = 12), 2 patients (16.7%) were in apparent remission, 7 (58.3%) had detectable Tg values without evidence of disease, 2 (16.7%) showed lymph node metastases in the mediastinum, and 1 patient (8.3%) died because of lung metastases. Of the 28 untreated patients, none with radiological evidence of disease, serum Tg off L-thyroxine therapy became undetectable in 19 cases (67.9%), significantly reduced in 6 cases (21.4%), and unchanged or increased in 3 patients (10.7%), 1 of whom developed lung metastases 14 yr after the diagnosis. In summary, our results indicate that in patients with detectable serum Tg and negative diagnostic (131)I whole body scan, treatment with high doses of (131)I may have therapeutic utility in patients with lung metastases and, to a lesser extent, in those with lymph node metastases. However, in view of the frequent normalization of Tg values in untreated patients, we believe that treatment with (131)I should be considered according to the result of the first posttherapy scan. If positive in the lung, (131)I treatment should be continued up to total remission; surgical treatment should be preferred in patients with node metastases, and no treatment should be used in those with thyroid bed uptake or no uptake.