Type I diabetes (T1D) is an organ-specific autoimmune disease caused by the T cell-mediated destruction of the insulin-producing β cells in the pancreatic islets. The onset of T1D is the consequence of a progressive destruction of islet β cells mediated by an imbalance between effector CD4⁢ T helper (Th)1 and regulatory CD4⁢ Th2 cell function. Since interferon-alpha (IFN-α) has been known to modulate immune function and autoimmunity, we investigated whether administration of adenoviral- mediated IFN-α gene would inhibit the diabetic process in NOD mice. The development of diabetes was significantly inhibited by a single injection of adenoviral-mediated IFN-α gene before 8 weeks of age. Next, we examined the hypothesis that Th2-type cytokines are associated with host protection against autoimmune diabetes, whereas Th1-type cytokines are associated with pathogenesis of T1D. The expression of IFN-α induced increase of serum IL-4 and IL-6 (Th2 cytokines) levels and decrease of serum IL-12 and IFN-γ (Th1 cytokines) levels. Therefore, overexpression of IFN-α by adenoviral- mediated delivery provides modulation of pathogenic progression and protection of NOD mice from T1D.