A method has been devised which is free of many of the shortcomings of serial epithyroid counting techniques as an index of the rate of thyroid hormone secretion. By means of this method, the effect of treatment with Lugol's iodine on the rate of thyroidal secretion of thyroxine (T₄) has been assessed in eight patients with thyrotoxicosis due to diffuse or multinodular goiter. The technique involves administration of a tracer dose of inorganic ¹²⁵I followed several days later by an intravenous tracer dose of ¹³¹I-labeled T₄. Serial observations of serum protein-bound (PB) ¹²⁵I and ¹³¹I are accompanied by frequent measurements of endogenous serum T₄ (T₄-¹²⁷I) concentration. Regardless of whether or not its administration was anteceded and accompanied by the administration of large doses of methimazole, iodine induced a rapid decrease in serum T₄-¹²⁷I concentration which could not be explained by an increase in the peripheral turnover of T₄, as judged from the metabolism of the ¹³¹I-labeled hormone. Hence, the decreased serum T₄ concentration could only have resulted from decreased secretion of the hormone by the gland. Analyses of specific activity relationships between PB¹²⁵I or T₄-¹²⁷I and PB¹³¹I made possible estimations of the extent to which iodine had decreased the rate of secretion of T₄. From such analysis, and in view of other considerations, it is concluded that the rapid decrease in T₄ secretion induced by iodine is not the result of an acute, sustained inhibition of T₄ synthesis, but rather results from an abrupt decrease in the fractional rate of thyroidal T₄ release.