There is a net loss of skeletal muscle protein in muscle-wasting disorders including the muscular dystrophies and denervation atrophy. Regardless of the nature of the underlying defect, a treatment that could reduce the rate of muscle protein degradation may be of therapeutic value in these conditions. Ketoleucine (α-ketoisocaproic acid) has been reported to reduce the rate of protein degradation in skeletal muscle. To evaluate ketoleucine's therapeutic potential, we studied its effect on the muscle protein loss that follows denervation in rats. Maximum tolerated doses of ketoleucine were administered twice daily to rats after surgical denervation of one leg. Wet weights and noncollagen proteins of the soleus and extensor digitorum longus muscles were measured. The ketoleucine-treated animals failed to show significant decrease in muscle wasting, compared with nontreated denervated controls. Further, urinary 3-methylhistidine excretion, a putative measure of muscle breakdown, was not reduced in ketoleucine-treated animals. Our findings do not support the suggested therapeutic role for ketoleucine in muscle-wasting disease.