Lipopolysaccharide (LPS) was used to simulate an endotoxemia model of muscle wasting in cultured muscle cells. HMB was shown to attenuate the LPS-induced protein degradation. HMB attenuated the activation of caspase-3/-8, activation of dsRNA-dependant protein kinase, and production of reactive oxygen species. This study further defined the mechanism whereby HMB may attenuate protein degradation in muscle wasting.