The disappearance of loading doses of thyroxine (T4) (100-20 000 microng T4 iv per rat weighing about 400 g) was measured with the aid of new technique allowing frequent blood sampling with maintenance of isovolaemia in anaesthetized animals. It was found that as early as 2 min after the injection more than half of the administered dose disappeared from the blood, while after 300 min only about 2% of that remained in the plasma. The direct relationship between the administered dose of T4 and both the relative and absolute level of free dialyzable T4 as well as of per cent of T4 displaced from plasma by sodium salicylate in vivo was demonstrated. Moreover, it was found that about 60% of administratered T4 is excreted by the bile within 300 min irrespective of the dose given, about 15 and 50% of that being found in the small intestine after 15 and 180 min, respectively. When two loading doses of T4 were subsequently administered and labelled with different isotopes, the amount of T4 from the first dose excreted by the bile was proportional to the amount of T4 from a second dose administered 18 h later. From all these observations it was concluded that, in vivo, an effective system for removal of the loading doses of thyroxine from the blood exists, and is presumably located in rapidly equilibrating tissues, mainly in the liver. From this point of view it appears that plasma protein carriers play an important role in the whole body economy of thyroxine, namely by maintaining a certain level in the blood to cover the actual functional needs of peripheral tissues.