The NOD mouse has been used to explore the many features of insulin-dependent diabetes mellitus (IDDM) that is caused by the destruction of insulin-producing beta cells in the islets of Langerhans of the pancreas. Self-reactive T cells have been considered to mediate IDDM in the NOD mouse, and antigen-presenting cells like DC and macrophages are expected to be involved in the processes from their role in generating regulatory or effector T cells. The present study shows that transfer of IFN-gamma-stimulated DC of the NOD or ICR mouse into the NOD mouse did not accelerate IDDM onset but afforded long-lasting protection against clinical and histological signs of IDDM in the recipient mice. The anti-diabetogenic ability was unique to IFN-gamma-stimulated DC when compared with unstimulated DC. A considerable proportion of the injected IFN-gamma-stimulated DC was demonstrated to migrate into the pancreas and its associated lymphoid tissues, suggesting the DC exert their anti-diabetogenic effects there. These findings suggest that development of autoimmune diabetes in the NOD mouse is under the control of DC, and that IDDM onset could be controlled by appropriately manipulating DC systems in vivo, which may open the gate for the therapeutic application of ex vivo-conditioned DC to human IDDM.