Abstract Type 1 diabetes (T1D) is characterized by the destruction of insulin producing β-cells in the pancreas mediated by IFNγ+ T cells. Non-obese diabetic (NOD) mice and T1D patients share similar characteristics of disease progression and the immune defects associated with disease, e.g., their dendritic cells (DC) produce elevated levels of pro-inflammatory cytokines such as IL-12, a cytokine that drives differentiation of IFNγ+ T cells. We have identified a new defect in DC in NOD mice, i.e., an abnormal accumulation of the transcription factor, β-catenin, which appears to be associated with the production of pro-inflammatory cytokines. Moreover, we found that DC isolated from T1D patients also expressed elevated levels of β-catenin compared to healthy individuals. To examine the function of β-catenin in DC, we either transfected human or murine DC with β-catenin siRNA or cultured them with an β-catenin inhibitor, and found that the production of pro-inflammatory cytokines (IL-12, IL-6, TNF) and subsequent production of IFNγ by T cells added to the DC culture was abrogated. Finally, treatment of NOD mice with an β-catenin inhibitor delayed onset and decreased incidence of disease. These data suggest that elevated expression of β-catenin in T1D may regulate the pro-inflammatory cytokine production in DC that subsequently drives induction of β-cell destroying T cells. Manipulation of β-catenin may, therefore, be a novel strategy for preventing and/or treating T1D.