Glucocorticoids causes muscle atrophy and weakness and but the mechanisms for these effects are unclear. The purpose of this study was to test a hypothesis that prednisone (Pred) counteracts insulin's anabolic effects on muscle. A randomized, double blind crossover design was used to test the effects of 6 days either Pred (0.8 mg/kg/d) or placebo use in 7 healthy young volunteers. Protein dynamics were measured across the leg using stable isotope tracers of leucine (Leu) and phenylalanine (Phe) after overnight fast and during a hyperinsulinemic (1.5 µU/min/kg FFM), euglycemic clamp with amino acid replacement. Fasting glucose, amino acids, insulin, and glucagon were higher (p<0.01) on Pred versus placebo while leg blood flow was 18% lower. However, basal whole body and leg kinetics of Leu and Phe were unaltered by Pred. Insulin infusion increased leg glucose uptake in both trials but was 65% lower with Pred than placebo. Insulin in both trials similarly suppressed whole body flux of Leu and Phe. Importantly, insulin increased net Leu and Phe balance across the leg, and the balance between muscle protein synthesis and breakdown, but these changes were 45-140% lower (p<0.03) in Pred than placebo. The present study demonstrates that short-term Pred use in healthy people does not alter whole body or leg muscle protein metabolism during the postabsoptive state but causes muscle insulin resistance for both glucose and amino acid metabolism, with a blunted protein anabolism. This interactive effect may lead to muscle atrophy with continued use of glucocorticoids.