In nonobese diabetic (NOD) mice, a deficiency in the number and function of invariant natural killer T-cells (iNKT cells) contributes to the onset of type 1 diabetes. The activation of CD1d-restricted iNKT cells by alpha-galactosylceramide (alpha-GalCer) corrects these deficiencies and protects against spontaneous and recurrent type 1 diabetes. Although interleukin (IL)-4 and IL-10 have been implicated in alpha-GalCer-induced protection from type 1 diabetes, a precise role for these cytokines in iNKT cell regulation of susceptibility to type 1 diabetes has not been identified. Here we use NOD.IL-4(-/-) and NOD.IL-10(-/-) knockout mice to further evaluate the roles of IL-4 and IL-10 in alpha-GalCer-induced protection from type 1 diabetes. We found that IL-4 but not IL-10 expression mediates protection against spontaneous type 1 diabetes, recurrent type 1 diabetes, and prolonged syngeneic islet graft function. Increased transforming growth factor-beta gene expression in pancreatic lymph nodes may be involved in alpha-GalCer-mediated protection in NOD.IL-10(-/-) knockout mice. Unlike the requirement of IL-7 and IL-15 to maintain iNKT cell homeostasis, IL-4 and IL-10 are not required for alpha-GalCer-induced iNKT cell expansion and/or survival. Our data identify an important role for IL-4 in the protection against type 1 diabetes by activated iNKT cells, and these findings have important implications for cytokine-based therapy of type 1 diabetes and islet transplantation.