Background and Hypothesis: At least 13 studies have shown that the ubiquitin-proteasome system mediates muscle wasting in weight-losing cancer subjects. We hypothesized that cancer itself may activate the ubiquitin-proteasome system, regardless of weight loss. Methods: We utilized hybrid mice obtained by crossing Mouse Mammary Tumor Virus-Transforming Growth Factor-α (TGF-α) mice with the Lepob strain. Five hybrid MMTV-TGF-α heterozygous Lep+Lepob female mice with mammary tumors were used; 4 nontransgenic heterozygous Lep+Lepob female mice served as controls. Ubiquitin conjugates were quantitated from hamstring and paraspinal muscles by Western blotting. Myocyte apoptosis was determined by a modified TUNEL assay. Results: All mice gained weight, even after tumor development. Higher concentrations of muscle ubiquitin conjugates were seen in the 5 tumor-bearing, TGF-α transgenic mice as compared with the 4 non-tumor-bearing mice: median (range) in arbitrary densitometric units: 0.67 (0.22-4.59) versus 0.18 (0.08-0.44) in hamstring muscle and 0.56 (0.23-20.15) versus 0.18 (0.08-0.25) in paraspinal muscle (p = 0.04 and p = 0.04, respectively; Mann-Whitney U test). Apoptosis was not seen in any muscle sample studied. Conclusions: Ubiquitin conjugates are increased in the skeletal muscle of tumor-bearing mice in the absence of weight loss. Such activation is not seen in the skeletal muscle on non-tumor-bearing mice. Further studies might focus of whether this observation is relevant to cancer-associated wasting of lean tissue.