Starvation depresses thyroid gland function. In addition, the peripheral turnover of thyroxine (T4) is reduced, in part due to decreased fecal elimination of T4. The present studies were performed to determine if starvation also affects the deiodinative pathway for T4 degradation. Rats were isotopically equilibrated with daily injections of exogenous [131-I]T4 while endogenous thyroidal T4 secretion and concentration of iodide were blocked with KCl04. Following a period of equilibration, either complete or 50% food deprivation was imposed on half the animals. Within 48 h of starvation, the serum T4 concentration of the fully starved rats doubled and remained high throughout. A marked decrease in fecal excretion of T4 was partially responsible for the increase. In spite of variability in the quantity of urinary 131-I excreted, the dieodinative clearance was consistently reduced. These effects were readily reversible upon resumption of normal feeding. Similar though less severe changes were observed in the half-fed rats. In both fully and partially-starved animals, the decreased dieodinative clearance in the face of increased serum T4 levels indicates a significant impairment of peripheral deiodination by some as yet unknown mechanism. In contrast, normal rats equilibrated with doses of T4 sufficient to increase serum T4 levels exhibit increased urinary clearance of iodide derived from T4. Thus the increased serum T4 levels are a consequence of impairment of the deiodinative pathway by starvation as well as decreased fecal T4 excretion. Clearly, voluntary alterations in food consumption must be controlled for differences between groups during experimental studies of T4 utilization.