This study describes an extrathyroidal mechanism for regulating serum concentration of triiodothyronine (T3) in thyroxine (T4) deficiency or excess. Serum levels of T3, T4, reverse T3 (rT3), and thyrotropin were determined in two series of athyreotic patients (n = 22 and n = 16, respectively) during various doses of T4 substitution therapy. The patients were followed from the severe hypothyroid state up to the modest hyperthyroid state, induced by stepwise increasing doses of administered T4. The periods of constant T4 replacement doses were 1 week (group I) and 5 weeks (group II), respectively. As serum T4 levels rose from less than 0.5 micrograms/dl to 18.9 micrograms/dl, serum T3 levels showed a curvilinear increase, which was pronounced in the very low T4 range while it was flattened at the higher end of the spectrum of T4 levels. As to rT3, an analogous course did not occur. The different character of the relationships between T4 and its conversion products was further elucidated by calculating the T3/T4 and rT3/T4 ratios. T3/T4 ratio declined fourfold from 43.3.10(-3) in the severe hypothyroid to 11.7.10(-3) in the hyperthyroid range. The results support the hypothesis of a peripheral autoregulation of T4 to T3 conversion which appears to be operative at both ends of the T4 spectrum and which serves to maintain or defend serum T3 levels.