Muscle wasting in cancer cachexia is associated with increased levels of malondialdehyde (MDA) in gastrocnemius muscles, suggesting an increased oxidative stress. To determine whether oxidative stress contributes to muscle protein catabolism, an in vitro model system, consisting of C₂C₁₂ myotubes, was treated with either 0.2 mM FeSO₄, 0.1 mM H₂O₂, or both, to replicate the rise in MDA content in cachexia. All treatments caused an increased protein catabolism and a decreased myosin expression. There was an increase in the proteasome chymotrypsin-like enzyme activity, while immunoblotting showed an increased expression of the 20S proteasome α-subunits, p42, and the ubiquitin-conjugating enzyme, E2_14k. These results show that mild oxidative stress increases protein degradation in skeletal muscle by causing an increased expression of the major components of the ubiquitin-proteasome pathway.