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Inflammatory damage contributes to beta cell failure in all forms of diabetes, yet few protective responses to inflammation have been described. Mitochondria are a frequent target of inflammatory β-cell damage, thus impairing bioenergetics and initiating the pro-apoptotic machinery. Thus, we hypothesized that clearance of damaged mitochondria by mitophagy is a necessary protective response for inflammatory β-cell damage. Utilizing live-cell imaging, biochemical assays, and in vivo mitophagy biosensors, we observed that pro-inflammatory cytokines promote trafficking of damaged mitochondria through the mitophagy pathway in mouse and human islets. Cytokine treatment dissipated mitochondrial membrane potential, decreased cellular respiration, induced recruitment of the mitophagy initiator Parkin, activated turnover of mitochondrial proteins, and ultimately, targeted damaged mitochondria to lysosomes for clearance. To determine if mitophagy acts as a protective response, we assessed the role of pro-inflammatory agents in mice deficient for T1D gene and mitophagy regulator Clec16a in β-cells. Indeed, Clec16a-deficient β-cells had increased cytokine-mediated apoptosis and worsening hyperglycemia after streptozotocin treatment in vivo as well as an accumulation of fragmented, damaged mitochondria. To explore mechanisms by which mitophagy contributes to cytokine-mediated toxicity, we found that reactive O2 species and nitric oxide (NO) activate mitophagy and that mitophagy-deficient mouse and human islets treated with anti-oxidants or NO inhibitors ameliorated β-cell death. Finally, we observed that adenoviral overexpression of Clec16a rescued cytokine-induced apoptosis in human islets. Together, our studies position mitophagy as a crucial protective response to inflammatory β-cell demise activated by both oxidative and nitrosative stress, which could be targeted to prevent β-cell death in diabetes. Disclosure V. Sidarala: None. S. Soleimanpour: None.