In the airway of inflammatory diseases, high level of HOCL (estimated to be as high as 8mM) can be generated through a reaction catalyzed by leukocyte granule enzyme- Myeloperoxidase (MPO). HOCL, a potent oxidative agent, causes extensive tissue injury through its reaction with various cellular substances including thiols, nucleotides and amines. Besides its physiological source, HOCL can also be generated by chlorine gas inhalation resulting from either an accident or potential terrorist attack. Despite the important role of HOCL induced airway epithelial injury, underlying molecular mechanism is largely unknown. In this study, we found that HOCL induced dose-dependent toxicity in airway epithelial cells. By transcription profiling using Genechip, a battery of HOCL inducible antioxidant genes was identified. And all of them have been reported previously to be regulated by nuclear factor erythroid-2 related factor 2 (Nrf2), a transcription factor that is critical to lung anti-oxidant response. In consistent to this finding, Nrf2 was found to be activated both time- and dose- dependent of HOCL treatment. Interestingly, although EGFR-MAPK pathway was also highly activated by HOCL, it was not involved in Nrf2 activation and Nrf2-dpendent gene expression. Instead, HOCL induced cellular oxidative stress appeared to directly lead to Nrf2 activation. To further understand the functional significance of Nrf2 activation, small interference RNA (siRNA) was used to either knock down Nrf2 level by targeting Nrf2 or enhance the nuclear accumulation of Nrf2 by targeting its endogenous inhibitor-Keap1. By both methods, we conclude that Nrf2 directly protects airway epithelial cell from HCOL-induced toxicity.