The effects of short-term (10 days) thyroxine administration (100 micrograms/kg body weight/die) on the BS, serum IRI and circulating FFA responses to slow, graded glucose stimulation were studied in dogs. The experiments reported demonstrated that the mean basal BS value in thyroxine-treated dogs is higher than that found in untreated controls, and that non-parallel mean BS responses to glucose infusion were observed during the test: the higher curve was found in the thyroxine-treated group. Mean basal serum IRI was similar in both groups, and parallel insulinemic responses to hyperglycemia were observed. Mean serum IRI responses as a function of time from the start of infusion to hyperthyroid dogs were lower than those observed in untreated controls. Mean basal serum FFA levels in both groups did not differ, and parallel serum FFA curves were found during the test. Thyroxine treatment caused a better lipogenic response to combined hyperglycemia/hyperinsulinemia and a steep subsequent rebound of serum FFA, as compared to untreated controls. We conclude that dogs with recently induced hyperthyroidism show an impairment in the net glucose uptake by tissues, a poor insulinemic response to glucose, a good lipogenic response and a sharp subsequent rebound of serum FFA. The high BS curve, the high tissue FFA response to insulin antagonists and the high mean BS level in the fasting condition might be accounted for by a thyroxine-induced active production of cAMP in body cells, but the low insulin secretion evidently is due to other mechanisms.