One of the long-term consequences of Type I diabetes is weight loss with muscle atrophy, the hallmark phenotype of cachexia. A number of disorders that result in cachexia are associated with immune deficiency. However, whether immune deficiency is a cause or an effect of cachexia is not known. This study examines the non-obese diabetic mouse, the mouse model for spontaneous Type I diabetes, as a potential model to study lymphopenia in cachexia, and to determine whether lymphopenia plays a role in the development of cachexia. The muscle atrophy seen in patients with Type I diabetes involves active protein degradation by activation of the ubiquitin-proteasome pathway, indicating cachexia. Evidence of cachexia in the non-obese diabetic mouse was determined by measuring skeletal muscle atrophy, activation of the ubiquitin-proteasome pathway, and apoptosis, a state also described in some models of cachexia. CD4+ T-cell subset lymphopenia was measured in wasting and non-wasting diabetic mice. Our data show that the mechanism of wasting in diabetic mice involves muscle atrophy, a significant increase in ubiquitin conjugation, and upregulation of the ubiquitin ligases, muscle RING finger 1 (MuRF1) and muscle atrophy F box/atrogin-1 (MAFbx), indicating cachexia. Moreover, fragmentation of DNA isolated from atrophied muscle tissue indicates apoptosis. While CD4+ T-cell lymphopenia is evident in all diabetic mice, CD4+ T cells that express a very low density of CD44 were significantly lost in wasting, but not non-wasting, diabetic mice. These data suggest that CD4+ T-cell subsets are not equally susceptible to cachexia-associated lymphopenia in diabetic mice.