Both GH and insulin-like growth factor I (IGF-I) have been shown to promote anabolism in human volunteers that are made catabolic by caloric restriction. We have used caloric restriction as a model of controlled catabolism to test the efficacy of these agents in reversing negative nitrogen balance. Six normal volunteers underwent caloric restriction for 2-week intervals. This restriction induced negative nitrogen balance (e.g. -239 mmol/day). During the second week either IGF-I (16 μg/kg h) was administered by intravenous infusion for 16 h, or GH (0.05 mg/kg) was given subcutaneously daily. GH alone improved nitrogen balance by 180 mmol/day, and IGF-I improved it by 175 mmol. The two hormones had opposite effects on carbohydrate metabolism. Mean blood glucose rose approximately 26% with GH whereas it fell 37% with IGF-I and the subjects had frequent hypoglycemic episodes during the infusion. Minimal complications were observed during the 6 days of IGF-I infusion and consisted primarily of edema and jaw pain. It appeared that IGF-I was as efficacious as GH in reversing the negative nitrogen balance induced by caloric restriction and that hypoglycemia induced by IGF-I was the major limiting factor. In a second study 7 volunteers underwent the identical caloric restriction. In contrast to the first study one treatment group received the combination of GH plus IGF-I given in exactly the same doses as in the first study. A second group received IGF-I alone. The combination of GH/IGF-I was much more potent in improving nitrogen balance. Specifically the subjects improved nitrogen balance by 260 mmol versus 170 mmol with IGF-I alone. Most of the nitrogen appeared to have entered the muscle compartment since urinary potassium excretion was also markedly reduced with GH/IGF-I. The effects on carbohydrate metabolism were divergent. The subjects who received combined treatment maintained normal glucose homeostasis and normal insulin and C peptide concentrations whereas the subjects who received IGF-I had suppression of C peptide and hypoglycemia. The combination of GH/IGF-I obviates several problems that occur with either GH or IGF-I alone. Carbohydrate metabolism is maintained at near-normal levels, and episodes of hypoglycemia are attenuated particularly if GH is administered prior to administering IGF-I. The combination is much more potent in terms of improving nitrogen balance suggesting that it will be a better therapy for subjects who have severe catabolic illnesses.