Whereas in the past a negative diagnostic 131I whole body scan (WBS) was interpreted as the lack of significant residual or recurrent thyroid cancer, today the patient with negative WBS and measurable serum thyroglobulin (Tg) presents a diagnostic and therapeutic dilemma. Previous studies have shown a high rate of visualization of uptake and a decrease in Tg after one or more therapeutic doses of 131I. In order to further assess the significance of this finding, retrospective analysis of patients with persistent thyroglobulinemia and negative WBS was performed for evidence of surgically amenable disease. Seven out of seventeen patients had neck ultrasound and/or computerized tomography (neck ± chest) showing the presence of pathologically confirmed malignant masses ranging from 1 to 4 cm in size. Their serum Tg while on L-thyroxine ranged between 2.4 and 1173 pmol/l. Removal of the identified masses resulted in a greater than 75% reduction in serum Tg in four out of five patients in the group. One patient achieved a serum Tg of < 1.5 pmol/1 while hypothyroid. Empiric 131I treatment of eleven patients with persistent thyroglobulinemia resulted in demonstrated uptake on post-therapy scan in seven. Further study is needed to compare the efficacy, safety and cost of a diagnostic approach to radiologically identify and surgically resect identified disease versus empiric therapeutic 131I treatment and high-dose WBS in this group of patients. Patients with negative WBS and persistent thyroglobulinemia, even to levels < 4.5 pmol/l, may have significant loci of thyroid cancer in surgically accessible areas. This suggests the need far a redefinition or clarification of the term 'recurrence' in thyroid cancer.