Whereas acute alcohol intoxication decreases muscle protein synthesis, there is a paucity of data on the ability of alcohol to regulate muscle protein degradation. Further, atrophic stimuli regulate proteolysis by increasing muscle-specific E3 ligases atrogin-1 and MuRF1 (i.e., atrogenes). Therefore, we tested the hypothesis that acute alcohol intoxication increases atrogene expression leading to an elevated rate of muscle protein breakdown. In male rats, the IP injection of alcohol dose- and time-dependently increased atrogin-1 and MuRF1 mRNA in gastrocnemius; a comparable change was absent in soleus and heart. The alcohol-induced increase in atrogene expression was independent of the route of administration (IP vs oral) as well as nutritional status (fed vs fasted) and gender (male vs female). The increase was independent of alcohol metabolism and over production of glucocorticoids, and could not be prevented by maintaining circulating IGF-I. Despite changes in atrogene mRNA, acute alcohol in vivo did not alter the release of either 3-methylhistidine (MH) or tyrosine from the isolated perfused hindlimb suggesting muscle proteolysis remains unchanged. Moreover, alcohol did not increase protein degradation in isolated epitrochlearis muscles or cultured myotubes. No increase in atrogene mRNA or 3-MH release was detected in muscle from rats chronically fed alcohol. Our results indicate that although acute alcohol intoxication increases atrogin-1 and MuRF1 mRNA in fast-twitch skeletal muscle, this change was not associated with increased proteolysis. Therefore, the loss of muscle mass/protein in response to chronic alcohol abuse results primarily from a decrement in muscle protein synthesis, not an increase in degradation.