Spontaneous development of diabetes in the nonobese diabetic (NOD) mouse is mediated by an immunological process. In disease-transfer experiments, the activation of diabetes has been reported to require participation of both CD4+ and CD8+ T-cell subsets. These findings seem to indicate that the CD4+ cells are the helper cells for the activation of cytotoxic CD8+ cells that directly destroy islet beta cells in type I diabetes. In this report we challenge this interpretation because of two observations: (i) Destruction of syngeneic islet grafts by spontaneously diabetic NOD mice (disease recurrence) is CD4+ and not CD8+ T-cell dependent. (ii) Disease recurrence in islet tissue grafted to diabetic NOD mice is not restricted by islet major histocompatibility complex antigens. From these observations we propose that islet destruction depends on CD4+ effector T cells that are restricted by major histocompatibility complex antigens expressed on NOD antigen-presenting cells. Both of these findings argue against the CD8+ T cell as a mediator of direct islet damage. We postulate that islet damage in the NOD mouse results from a CD4+ T-cell-dependent inflammatory response.