In type 1 diabetes, many effector mechanisms damage the β cell, a key one being perforin/granzyme B production by CD8+ T cells. The death receptor pathway has also been implicated in β cell death, and we have therefore generated NOD mice that express a dominant-negative form of the Fas-associated death domain protein (FADD) adaptor to block death receptor signaling in β cells. Islets developed normally in these animals, indicating that FADD is not necessary for β cell development as it is for vasculogenesis. β cells from the transgenic mice were resistant to killing via the Fas pathway in vitro. In vivo, a reduced incidence of diabetes was found in mice with higher levels of dominant-negative FADD expression. This molecule also blocked signals from the IL-1R in culture, protecting isolated islets from the toxic effects of cytokines and also marginally reducing the levels of Fas up-regulation. These data support a role for death receptors in β cell destruction in NOD mice, but blocking the perforin/granzyme pathway would also be necessary for dominant-negative FADD to have a beneficial clinical effect.