Treatment of hyperlipidemia with clofibrate may result in development of a muscular syndrome. Our previous investigation (1979. J. Clin. Invest.64: 405.) showed that chronic administration of clofibrate to rats causes myotonia and decreases glucose and fatty acid oxidation and total protein of skeletal muscle. In the present experiments we have investigated amino acid and protein metabolism in these rats. Clofibrate administration decreased the concentration of all three branched-chain amino acids without affecting those of others in muscle. Studies to examine the mechanism of decreases in muscle concentrations of branched-chain amino acids showed the following: (a) Plasma concentration of leucine was decreased, whereas there was no significant change in the concentration of isoleucine and valine. (b) Liver concentrations of all three branched-chain amino acids remained unaltered. (c) The uptake of cycloleucine (a nonmetabolizable analogue of leucine) by both muscle and liver was unaffected. (d) The percentage of a trace amount of injected [1-(14)C]leucine expired as (14)CO(2) in 1 h was significantly increased. (e) The capacity of muscle homogenate for alpha-decarboxylation of leucine was enhanced, whereas that of liver was unaffected. (f) The activity of leucine transaminase was unaffected, whereas that of alpha-ketoisocaproate dehydrogenase was increased in muscle. Studies of protein synthesis, carried out as incorporation of leucine into protein and corrected for differences in specific activity, showed no alteration in liver but enhanced synthesis in muscle of clofibrate-fed rats. Clofibrate stimulated muscle protein degradation, which was demonstrated by increased tyrosine release from gastrocnemius muscle slices and by increased urinary excretion of 3-methylhistidine. We conclude that (a) clofibrate treatment increased branched-chain amino acid oxidation by increasing the activity of branched-chain alpha-ketoacid dehydrogenase in the muscle, (b) increased oxidation results in selective decreases in the concentration of these amino acids in muscle, and (c) decreases in branched-chain amino acid concentration may be responsible for increased protein degradation in muscle.