The redox status of macrophages (M phi), indexed by intracellular content of glutathione (icGSH), varies sequentially along with disease progression in nonobese diabetic mice. At the stage of early insulitis, M phi skew to oxidative M phi (OM phi) with decreased icGSH, then to reductive M phi (RM phi) with elevated icGSH and to OM phi after the occurrence of diabetes. RM phi or OM phi inducing agents either delayed or accelerated the onset of diabetes in a mutually inverse manner. RM phi or OM phi adoptively transferred exacerbated or ameliorated the disease progression depending on the redox status of M phi of recipient mice. The new paradigm that the sequential conversion of redox status of M phi dictates the pathological progression may provide a new insight on the mechanism underlying autoimmune diabetes.