1. Splanchnic exchange of glucose, lactate, pyruvate, glycerol and individual plasma amino acids was determined in five clinically unaffected monozygotic twins of insulin-dependent diabetics and in a group of five age- and sex-matched controls. The studies were performed in the postabsorptive state and after stimulation of endogenous insulin secretion by the intravenous infusion of glucose at a rate of 2 mg/min per kg for 45 min. 2. In the basal state the mean splanchnic glucose output was 25% lower for the twins than for the controls while splanchnic uptake of glucose precursors was similar in the two groups. The concentration of circulating insulin (which rose by no more than 10–15 μunits/ml in either group) was lower during the infusion in the twins than in the controls. Despite the lower insulin concentrations, infusion of glucose resulted in a complete shut off of splanchnic glucose production in the twins, while in the controls only a 50% inhibition of basal glucose output was observed. In both the twins and controls estimated peripheral glucose utilization was unchanged during the glucose infusion. 3. It is concluded that: (a) in clinically unaffected identical twins of known diabetics basal splanchnic glucose production is reduced while uptake of glucose precursors is unchanged, suggesting a diminished contribution to basal glucose output from hepatic glycogenolytic processes; (b) in the twins as well as in controls, the liver is the primary site of action of small increments in endogenous insulin; (c) hepatic sensitivity to endogenous insulin is augmented in twins as compared with controls.