Type 1 diabetes is an autoimmune disease characterized by T cell-mediated destruction of pancreatic islet beta cells. Pancreatic islet transplantation with long-term immunosuppressive drug treatment is an accepted therapeutic option for patients with type 1 diabetes suffering from disabling hypoglycemia on insulin treatment. Here we investigated the replacement of immunosuppressive drug treatment with immune tolerance establishment induced by temporary B cell-depletion therapy for islet transplantation. The result suggested that the combined therapy of B cell depletion and syngeneic islet transplantation may reverse the disease in hCD20/NOD mice.