Reactive oxygen species, including hydrogen peroxide (H(2)O(2)), can cause toxicity and act as signaling molecules in various pathways regulating both cell survival and cell death. However, the sequence of events between the oxidative insult and cell damage remains unclear. In the current study, we investigated the effect of oxidative stress on activation of the Receptor for Advanced Glycation End-products (RAGE) and subsequent protection against H(2)O(2)-induced pancreatic tumor cell damage. We found that exposure of pancreatic tumor cells to H(2)O(2) provoked a nuclear factor kappa B (NF-κB)-dependent increase in RAGE expression. Further, suppression of RAGE expression by RNA interference increased the sensitivity of pancreatic tumor cells to oxidative injury. Furthermore, targeted knockdown of RAGE led to increased cell death by apoptosis and diminished cell survival by autophagy during H(2)O(2)-induced oxidative injury. Moreover, we demonstrate that RAGE is a positive feedback regulator for NF-κB as knockdown of RAGE decreased H(2)O(2)-induced activity of NF-κB. Taken together, these results suggest that RAGE is an important regulator of oxidative injury.