Seventeen patients with papillary thyroid cancer whose serum thyroglobulin (Tg) levels were elevated when hypothyroid, but whose diagnostic whole body scans were negative, were treated with 150-300 mCi 131I. All patients had total thyroidectomy and 131I ablation for thyroid remnants. Before the study, 9 patients had 131I therapy for tumor recurrence and/or metastases, and 5 patients had excisions of nonfunctioning metastasis. Radiological studies did not reveal evidence of metastases. In the initial evaluation, Tg levels ranged from 8-480 ng/mL (24 pmol/L to 1.5 nmol/L), and posttherapy whole body scans (RxWBS) revealed undiagnosed local recurrence and/or metastases in 16 of 17 patients. Follow-up from 6 months to 5 yr is available in 16 patients. RxWBS after a second treatment was positive in 8 of 13 patients, and after a third treatment in 5 of 5 patients, although in 3 cases, uptake in distant metastasis had disappeared. In 8 patients, Tg fell to 5 ng/mL or less. In 1 patient, RxWBS became negative, but Tg remained elevated; subsequent treatment revealed local and mediastinal uptake, but previous lung uptake had disappeared. In 8 patients, RxWBS remains positive, and elevated Tg persists. A total of 35 RxWBS were performed; 29 were positive. Follow-up Tg concentrations decreased in 81% of patients after the first treatment, in 90% after the second treatment, and in 100% of the patients after the third treatment. Tg (mean +/- SE) decreased from 74 +/- 33 ng/mL in the first evaluation to 62 +/- 32 ng/mL in the second study and 32 +/- 20 ng/mL in the third study. The therapeutic effectiveness of 131I treatment in patients with elevated Tg and negative diagnostic whole body scans is indicated by the conversion to negative RxWBS, the statistically significant decrease in the mean Tg level, and the reduction of serum Tg to 5 ng/mL or less in 50% of patients. Further experience with this therapeutic approach is required to evaluate its effectiveness in improving prognosis and survival.