The aim of this study was to examine the temporal and dose characteristics of the corticosteroid-binding globulin (CBG) response to T4 and to determine whether this response is due to stimulation of hepatic biosynthesis of CBG. When n-propylthiouracil (PTU)-induced hypothyroid pups were given a single injection of T4 (0.1 microgram/g BW) on postnatal day 5, 6, or 7, only pups treated on day 7 showed a significant increase in CBG. In a T4 dose-response study conducted with 5- and 8-day-old pups, older pups exhibited maximum CBG concentrations (Rmax) which were 2.5-fold higher than those of younger pups. The D1/2 (dose required to elicit half the maximum response) values were similar at both ages. The effect of T4 withdrawal on serum CBG was also studied in PTU-treated pups. T4 injection on postnatal days 5-19 resulted in a progressive rise in CBG. In pups treated with T4 on days 5-9 and then withdrawn from treatment through day 20, serum CBG showed no further increase but was maintained at an elevated level. Using a liver slice system to assess CBG production in vitro, livers from 14-day-old hyperthyroid pups produced 4.77 ng corticosterone bound/g liver, while livers from euthyroid pups produced no CBG. We conclude: 1) the response of CBG to T4 is a function of the age of the animal; between days 5 and 8 this is due to increased Rmax without any change in sensitivity to T4 (D1/2); 2) T4 is required not only to initiate but also to sustain the developmental increase in CBG; and 3) T4 elicits an increase in circulating CBG by stimulating its synthesis.