The effect of short-term prednisone administration (40 mg daily) on thyroxine (T4) distribution has been studied in 16 subjects with different categories of thyroid function: Group I, Normal; Group II, Newly diagnosed or recurrent hyperthyroidism; Group III, Treated hyperthyroidism; and Group IV, Treated myxedema. Studies included measurement of t½ of acute disappearance and peripheral turnover of T4-131I, hepatic volume (HV), clearance (HC) and content (QH) of T4; T4 binding globulin (TBG) and T4 binding prealbumin (TBPA). There was essentially no change in free fraction of serum T4 in 4 subjects in whom this was measured. Acute disappearance of T4-131I slowed in all the subjects (13/13). The fractional turnover rate of T4 (k) diminished in 10, was unchanged in 3 and increased in 2 subjects. The daily rate of T4 disposal (D) decreased in 12, increased in 1, and was unchanged in 2 subjects. HV of T4 decreased in 10 and was unchanged in 2 subjects. HC decreased in 9 subjects and increased in 3. QH of T4 decreased in 12 subjects in whom this was measured. TBPA increased in all subjects, but changes in TBG were generally slight and variable. It is shown that increase in TBPA cannot alone explain the observed changes in T4 kinetics and the suggestion is made that glucocorticoids primarily alter the hepatic metabolism of T4, which in turn contributes to the observed changes in its peripheral distribution.