It has been suggested that leucine and alpha-ketoisocaproic acid (KIA) stimulate protein synthesis and reduce protein breakdown and may be useful in the treatment of muscle catabolism during sepsis. However, whether leucine and KIA regulate protein turnover in septic skeletal muscle is not known. In this study, intact muscles from untreated normal rats or from rats subjected to cecal ligation and puncture were incubated in the presence of leucine or KIA. In normal muscle, leucine stimulated protein synthesis and reduced protein degradation, while KIA decreased protein breakdown. In septic muscle, protein synthesis was also stimulated by leucine, but only at a concentration higher than that needed to affect protein synthesis in normal muscle. Protein breakdown in septic muscle was unaffected by leucine and KIA even at an extracellular concentration as high as 5 mmol/L. Since other experiments showed that the intracellular concentration of leucine was not different in incubated normal and septic muscles, these results suggest that sepsis induces changes in skeletal muscle protein turnover that are resistant to the effects of leucine.