The efficacy of iodide and thyroxine in ameliorating the several deficiencies occasioned by thyroidectomy in male and female rats was compared in order to obtain indirect evidence for extrathyroldal thyroxine formation. More direct refutation of the opposing concept that iodide simulates the action of thyroxine was also sought in experiments with propylthiouracil (PTU) and tribromothyronine. In all indices of thyroxine action examined in thyroldectomized rats, namely, growth, metabolic rate, heart rate, and pituitary, adrenal and reproductive function, the restorative or maintenance activities of large quantitites of iodide were identical with those of minute quantities of thyroxine. Effective doses of iodide presumably resulted in the formation of thyroxine in quantities equivalent to the dally injection of 0.25-0.5 /[mu]g. PTU abolished most of the growth response to iodide, while not interfering with the action of thyroxine, which provided even more cogent evidence that the responses obtained were due to the formation of thyroxine. To further support the inference that the inhibitory influence of PTU was exercised through interference with iodothyronine formation rather than interference with the extra-thyroidal intracellular oxidation of iodide to the potentially active substance iodine, it was necessary to analogize with the effects of tribromothyronine and bromide. Since tribromothyronine possessed high biological activity in thyroidectomized rats while bromide was inactive, it was concluded that the iodothyronine molecule functions in some manner other than that of a simple transmembrane transport system for oxidizable iodide. Although the results strongly suggest that extrathyroidal thyroxine formation does occur in the rat, these lines of evidence are still circumstantial.