Current evidence suggests that reactive oxygen species (ROS) may participate in the destruction of pancreatic β-cells leading to type 1 diabetes. Genetic factors predisposing individual susceptibility to type 1 diabetes might therefore include those affecting the efficacy of ROS metabolism. In a direct in vivo test of this hypothesis, we have generated strains of mice carrying trans-genes that supplement basal levels of the radical-scavenging enzyme Cu/Zn Superoxide dismutase in the pancreas via directed expression in β-cells. Expression of these transgenes significantly enhances resistance to alloxan-induced diabetogenesis above that of control animals, thereby providing direct in vivo evidence that genetic variation in ROS metabolism can affect susceptibility to oxidative stress-mediated diabetogenesis.