Low thyroxine-binding globulin (TBG) capacity was found in seven members of a family in four generations. The effect on peripheral metabolism, as measured by the basal metabolic rate (BMR), of single 1000 μg intravenous doses of sodium L-thyroxine (T4) and sodium L-triiodothyronine (T3) was studied. In TBG deficient patients and those loaded with diphenylhydantoin (DPH) so that the PBI was depressed to low levels, T4 produced an effect on the BMR within 2–5 days similar in rapidity of onset and magnitude to that produced by T3 in all subjects. In normal controls or patients on maintenance DPH therapy, T4 produced little or no effect on the BMR within 8 days. The calorigenic studies were compared mainly in the TBG deficient patient with the acute (20–50 min) disappearance from plasma as well as with the chronic fate of the 131I-labelled hormones. The acute and chronic disappearances of T4 were more rapid in the TBG deficient patients whereas the acute and chronic disappearances of T3 were similar to that of subjects with normal TBG. These observations support the hypothesis that in normal humans TBG acts as a rate-regulating factor in the peripheral metabolism of acutely administered T4 by limiting the access of T4 to the tissues, thereby slowing its action on the cell. Therefore, the difference in peripheral metabolic effect of T4 and T3 would appear to be related to the presence of TBG in human plasma.