The role of tumor necrosis factor alpha (TNF-alpha) in the pathogenesis of autoimmune diabetes mellitus was tested in the nonobese mouse (NOD) model system. The effects of TNF-alpha were assessed on three levels: (i) insulitis development, (ii) development of overt diabetes, (iii) adoptive transfer of diabetes by splenic lymphocytes. Spontaneous diabetes mellitus was blocked in NOD mice by long-term treatment with recombinant TNF-alpha. Treatment with TNF-alpha caused a significant reduction in the lymphocytic infiltration associated with the destruction of the insulin-producing beta cells. Class II major histocompatibility complex Ia expression by islet cells was not up-regulated by TNF-alpha. Moreover, TNF-alpha was able to suppress the induction of diabetes in adoptive transfer of lymphocytes from diabetic female mice to young nondiabetic male NOD mice. These activities of TNF-alpha were shared by interleukin 1 alpha in this system. These studies have implications for the pathogenesis and therapy of autoimmune diabetes mellitus.