Arterial concentrations and splanchnic exchange of glucose, amino acids, lactate, pyruvate, and glycerol were determined in 14 hyperthyroid patients and 12 healthy controls. Seven of the patients were restudied after 5-12 mo of medical management at which time there was chemical and clinical evidence of a euthyroid state. The arterial level of glucose was slightly higher (+10%) in the patient group and the glycerol concentration was three times greater among the patients. The plasma levels of the glycogenic amino acids, alanine, glycine, and serine were decreased by 20-30%, while the concentrations of leucine, isoleucine, and tyrosine were increased by 20-80%. The levels of lactate and pyruvate were similar in patients and controls as were insulin and glucagon concentrations. Splanchnic glucose output in the patient group was 35% lower than in controls. However, total splanchnic uptake of glucogenic precursors was 100% higher than in controls and showed a direct linear correlation with serum triiodothyronine. Total precursor uptake could account for 75% of splanchnic glucose output in the patients, compared to 26% in controls. The increase in uptake of lactate, alanine, and other amino acids was due to a 35-80% rise in splanchnic fractional extraction plus a 20% rise in estimated hepatic blood flow. When the patients were restudied after medical treatment splanchnic exchange of glucose and glucose precursors had reverted to normal values. The present findings demonstrate that in hyperthyroidism (a) total splanchnic glucose output is reduced in relation to controls, (b) splanchnic uptake of gluconeogenic precursors is accelerated, largely due to a rise in fractional extraction of precursor substrates and to a smaller extent, as a result of an increase in hepatic blood flow, and (c) these changes revert to normal when a euthyroid state has been achieved.