Serum thyroglobulin (Tg), triiodothyronine (T3), and thyroxine (T4) concentrations were measured in sera from selected patients with hyperthyroidism due to Graves' disease and with subacute thyroiditis. In agreement with previous reports, the concentration of serum Tg was elevated in untreated hyperthyroidism due to Graves' disease, being 132 +/- 124 ng/ml (mean +/- SD) as opposed to 11 +/- 6.4 ng/ml in normal subjects. During treatment of hyperthyroidism with antithyroid drugs with or without iodide, reductions in thyroid hormone concentrations were not associated with a change in serum Tg. On the other hand, marked elevations in serum Tg to concentrations as high as 7000 ng/ml were observed within 24-48 hr after subtotal thyroidectomy or 131I treatment of patients with Graves' disease. These abrupt 10-50-fold increases in serum Tg were not associated with changes in serum T3 and T4. As previously demonstrated, patients with subacute thyroiditis may have elevated serum Tg concentrations that are not associated with elevations in serum T3 and T4. Serum Tg may remain elevated long after clinical and other biochemical mainfestations of this disease have disappeared. These data suggest that the disruption in thyroid function in patients with subacute thyroiditis may persist in a subclinical form for longer periods than previously suspected. Serum Tg appears to be a sensitive indicator of acute thyroidal damage due to surgical, radiation, or inflammatory trauma. The absence of parallel changes in serum Tg, T3, and T4 indicates that release of these thyroidal components can occur by different mechanisms and that nonthyroid tissues cannot efficiently generate T3 and T4 from circulating Tg. Accordingly, local or systemic stimulation of thyroidal Tg hydrolysis may be involved in the generation of hyperthyroidism sometimes seen in patients with subacute thyroiditis.