To evaluate the effects of substrate and hormonal background on the peripheral response to methionyl human growth hormone (met-hGH), metabolic measurements were performed in 10 normal subjects before and at the end of a 6-hr infusion of met-hGH. Five subjects were studied in the postabsorptive state and five were studied on the 10th day of intravenous repletion. Measurements of hormonal levels, serum amino acid levels, and free fatty acid levels, as well as extremity amino acid and free fatty acid fluxes, were performed. Met-hGH in the postabsorptive setting had no effect on extremity amino acid flux but significantly increased extremity free fatty acid efflux. In contrast, met-hGH in the background of intravenous feeding produced a significant extremity uptake of total amino acids but had no effect on free fatty acid flux. These data suggest a relationship between the substrate background and the actions of met-hGH on both peripheral protein and lipid metabolism. Therefore, the adequacy and composition of the feeding regimen may be important when considering growth hormone as an adjunct to nutritional therapy.