Insulin-dependent diabetes mellitus is an autoimmune disease, under polygenic control, manifested only when >90% of the insulin-producing β cells are destroyed. Although the disease is T cell mediated, the demise of the β cell results from a number of different insults from the immune system. It has been proposed that foremost amongst these effector mechanisms is CD95 ligand-induced β cell death. Using the nonobese diabetic lpr mouse as a model system, we have found, to the contrary, that CD95 plays only a minor role in the death of β cells. Islet grafts from nonobese diabetic mice that carry the lpr mutation and therefore lack CD95 were protected only marginally from immune attack when grafted into diabetic mice. An explanation to reconcile these differing results is provided.