The relationships among the content and composition of soluble iodoproteins in thyroid gland, the serum Tg concentration and the morphological structure of gland were investigated in guinea-pigs during short-term and long-term TSH administration (2 I.U. per day for 1 to 28 days). A significant decrease in the content of Tg in the gland (from 6.50 mg to 1.32 mg/100 mg tissue), disappearance of 12 S iodoprotein, hypertrophy and hyperplasia of the follicular cells were observed in guinea-pigs treated with TSH up to 7 days. Later on, after depletion of follicular colloid, reaccumulation of colloid in the preexisting and newformed follicles (a marked increase of Tg and 12 S protein) and partial involution of the structural changes occurred. The serum Tg concentration increased during the whole period of TSH treatment (mean values from 100 to 500 micrograms/l). A marked positive correlation between serum Tg concentration and thyroid weight was found. Serum T3 and T4 concentrations increased transiently with maximal values on the 1st day (T3, from 0.86 to 3.26 nmol/l, T4, from 44 to 138 nmol/l) and decreased thereafter. The results imply that different regulatory mechanisms exist which control thyroid hormone secretion and transfer of Tg from the gland into blood circulation. The serum Tg level is directly dependent on the total bulk of thyroid tissue, but is considerably less dependent on the structure of the gland. The reaccumulation of colloid (Tg) in thyroid follicles of guinea-pigs treated with TSH is a result of the reduction of the stimulatory effect of TSH on the process of Tg degradation during chronic hormone application. Several different factors may be responsible for the appearance of refractoriness or desensitization of the thyroid to prolonged exogenous TSH stimulation.