A B S T R A C T Studies of the possibility that thyroxine (T4) is converted to 3,5,3'-triiodo-L-thyronine (T3) in the extrathyroidal tissues in man have been conducted in 13 patients, all but two of whom were athyreotic or hypothyroid, and all of whom were receiving at least physiological replacement doses of synthetic sodium-Lthyroxine.T3 was found in the sera of all patients, in concentrations ranging between 243 and 680 ng/100 ml (normal range 170-270 ng/100 ml). These concentrations were far in excess of those which would have been expected on the basis of the T3 contamination of the administered T4, as measured by the same technique employed in the analysis of serum. When oral medication was enriched with 'I-labeled T4 for 8 or more days, labeled T3 and tetraiodothyroacetic acid (Tetrac or TA4) were found in the serum to the extent of approximately 2-5% of total radioactivity, as assessed by unidimensional paper chromatography. The same results were obtained with a specially purified lot of radioactive T4 containing less than 0.1% T3 as a contaminant. The identities of the 'I-labeled T3 and TA4 were verified by two-dimensional chromatography as well as by specific patterns of binding in serum. The labeled T3 isolated was bound by albumin and by T4-binding globulin (TBG), but not by T4-binding prealbumin (TBPA); in contrast the labeled TA4 was bound by albumin and TBPA, but not by TBG.To exclude the possibility that the conversion of T4 to T3 was a peculiarity of the oral route of administra- There is no doubt whatsoever that at least a portion of the T3 in the blood results from direct secretion by the thyroid gland, T3 having been found in the thyroid venous effluent, and in concentrations substantially higher than in the concurrently sampled arterial blood (4, 5). What has remained uncertain, however, is what fraction, if any, of the T3 in the blood arises from the