Although alloxan-resistant (ALR) mice share 70% of the NOD genome, ALR islets are remarkably resistant to oxidative stress and autoimmunity. Using 2D PAGE comparative analysis, we have characterized 55 proteins that are differentially expressed between the NOD and ALR islet proteome. Ten proteins were found to be highly expressed in the NOD islets. Typically, proteins associated with pancreatic inflammation and autoimmunity, such as amylase and carboxypeptidase, are highly expressed in the NOD islets. Forty-five proteins showed significantly higher expression in the ALR islets. Among these, 30 are proteins implicated in the regulation of intracellular stress including heat-shock proteins, disulfide isomerase-associated proteins, ROS detoxification enzymes, and apoptotic regulators. Our results clearly demonstrate that the 30% unique ALR genome encodes protective determinants expressed at islet levels, which render the islets of this strain of mice resistant to oxidative stress and autoimmunity.