Normal and adrenalectomized rats treated with cortisone lost 2% of their initial body weight per day, whereas controls gained weight at a rate of 2%/day. Five days of treatment resulted in a 25% reduction in the weights of a number of mixed fiber type muscles, but did not affect the weights of heart or soleus, a muscle consisting of slow-twitch red fibers. Reductions in muscle weights were accompanied by a loss of protein and RNA. Perfused hemicorpus preparations from rats receiving 5 days of treatment released several amino acids in greater amounts than the controls. Protein synthesis in perfused gastrocnemius was reduced 50-60% after 3 or 5 days of steroid treatment. This reduction was due to a loss of RNA and to an inhibition of translation resulting from an impairment in peptide-chain initiation. In contrast, RNA content and initiation were not altered in heart and soleus. Protein degradation in perfused hemicorpus and cathepsin D activity in gastrocnemius were unaffected by cortisone treatment, suggesting that loss of muscle weight and protein content as well as increased amino acid release resulted from the reduction in protein synthesis.