In recent years suppression tests with a single dose of 3 mg 1-thyroxine (T4) and weekly doses of 1 mg T 4 in the treatment of hypothyroidism have been put to clinical trial and the lack of side-effects of such high doses (5 to 15 X daily requirements) was stressed. Hence, it was decided to study the absorption of 1-T-4 from the gastrointestinal tract and its metabolism in euthyroid patients. Doses from 250 to 2500 mug T 4, mixed with 250 muCi 131I-thyroxine were given to 10 patients. After the thyroid had been blocked with perchlorate, the excretion was followed in faeces and urine for 4 to 5 days, the thyroid uptake of 131I was checked and serial blood samples were drawn to follow plasma activity curves. Quantitative analyses of T 4, triiodothyronine (T 3), ETR and TSH were also performed on the plasma samples, whilst paper chromatography of urine samples allowed a further separation of iodide and organic iodine compounds. The results showed a definite rise in plasma T 4 levels after administration of large T 4 doses, with a simultaneous increase in T 3 values. Doses of 2500 mug T 4 temporarily produce abnormally elevated plasma T 4 and ETR values, whilst T 3 increases to the upper limit of the normal range. The relatively moderate reaction of the mentioned parameters following the administration of large T 4 doses can be partly explained by the considerably lower faecal excretion of T 4 with doses of 250 mug T 4 than with high T 4 doses. There is also an intensive binding of T 4 to TBG up to single doses of 1000 mug T 4, which provides an adequate metabolic "buffer" and declines only after saturation of the TBG binding capacity at higher dosage. Moreover, larger doses of T 4 are metabolized quicker than smaller ones. The above-mentioned results allow the following conclusions: 1. Very large single doses of T 4 (2500 to 3000 mug) are less easily absorbed from the gastrointestinal tract than "physiological" doses. 2. The degradation of T 4 at high dosage is quicker than at lower dosage. 3. The intensive binding of T 4 to TBG explains the lack of side effects with large doses of orally-administered T 4. 4. On the basis of the present data single doses of 500 to 1000 mug T 4 can be recommended for therapeutic purposes.