The follow-up of differentiated thyroid cancer after total thyroidectomy and thyroid ablation is commonly based on serum Tg determination and 131-iodine ((131)I) diagnostic whole-body scan (WBS) performed in the hypothyroid state, 6-12 months after thyroid ablation. Based on the greater sensitivity of Tg measurement, with respect to WBS, the diagnostic yield of diagnostic WBS has been questioned in patients who are off L-T(4) therapy and have undetectable Tg levels. The aim of the present retrospective study was to evaluate the diagnostic relevance of (131)I WBS performed after thyroid remnant ablation, in patients with undetectable serum Tg and off thyroid hormone therapy. The study included 315 of 662 consecutive patients (47.6%) treated in our department between 1980 and 1990, who, at the first control WBS after thyroid ablation, had undetectable serum Tg levels in the hypothyroid state. There were 54 men (17%) and 261 women (83%), with a mean age of 40.9 +/- 13.1 yr (range, 12-76), followed for a mean of 12 +/- 2.8 (range, 9-19) yr. The control WBS was negative in 225 (71.4%) patients and positive for persistent areas of thyroid bed uptake, frequently of very low significance, in 90 (28.6%). No local or distant metastases were discovered. At the last follow-up visit (1999-2000), 281 (89.2%) patients showed complete remission, with undetectable serum Tg off L-T(4) and negative WBS. Persistent thyroid bed uptake, with undetectable levels of Tg, was observed in 29 patients (9.2%) studied during L-T(4) withdrawal. Only 2 patients (0.6%) experienced local recurrence (lymph-node metastases) during their follow-up. In conclusion, our data suggest that the presence of undetectable levels of serum Tg off L-T(4) at the time of the first control WBS after initial treatment, is highly predictive of complete and persistent remission. With the exception of detecting persistent thyroid bed uptake in a minority of cases, the control WBS has never given information that could influence the following therapeutic strategy. On this basis, we propose that the diagnostic (131)I WBS may be avoided in patients with undetectable levels of Tg off L-T(4). These patients may be monitored with clinical examination, neck ultrasound, and serum Tg measurements on L-T(4).