Abstract Cytokine-induced β cell destruction may be mediated by the generation of nitric oxide and/or reactive oxygen species. The relative importance of NO and ROS in cytokine-induced β cell pathophysiology remains unclear. This investigation evaluates and contrasts the cytoprotective potential of antioxidant gene transfer, versus NF-κB inhibition, using a degradation-resistant mutant of IκBα. NF-κB inhibition conferred significant protection against cytokine-induced damage whereas antioxidant overexpression failed to provide protection. Conferred cytoprotection was associated with a suppression of iNOS activation and nitrite accumulation. Our data implicates iNOS, as opposed to ROS, as the pivotal player in cytokine-induced β cell damage. From a therapeutic standpoint, strategies aimed at targeting the activation of iNOS may harbor therapeutic potential in preserving beta cell survival in the face of proinflammatory cytokine exposure.