Immunization against extracellular neurotoxic proteins has shown promise in the treatment of several neurodegenerative disorders. We sought to determine whether immunization against mutant huntingtin, the intracellular protein that causes Huntington's disease (HD), could slow disease progression in the HD mouse model HDR6/2. DNA vaccination was used to present the mutant intracellular antigen to the immune system in a physiological context. Assay of a peripheral biomarker, pancreatic insufficiency, was used as an initial test of efficacy. DNA vaccination with a 5' fragment of the HD cDNA prevented development of the HDR6/2 diabetic phenotype. Insulin staining demonstrated that HDR6/2 diabetes may be caused by a severe pancreatic insulin deficiency. Immunoresponsive HDR6/2 mice showed increased insulin staining more closely resembling wild-type levels. These observations suggest that DNA vaccination against toxic intracellular proteins may be therapeutic.