Oxidative stress has been implicated in allergic responses. SHP-1 is a target of oxidants and has been reported as a negative regulator in a mouse model of asthma. We investigated the effect of oxidative stress on the development of allergic airway inflammation in heterozygous viable motheaten (mev/+) mice deficient of SHP-1. Wild type (WT) and mev/+ mice were compared in this study. Human alveolar epithelial cells (A549) transfected with mutant SHP-1 gene were used to evaluate the role of SHP-1 in lung epithelial cells. Hydrogen peroxide (H₂O₂) and Paraquat were used in vitro and in vivo, respectively. We also investigated whether mev/+ mice can break immune tolerance when exposed to aeroallergen intranasally. Compared to WT mice, bronchoalveolar lavage cells and splenocytes from mev/+ mice showed a different response to oxidant stress. This includes a significant enhancement of intracellular ROS and STAT6 phosphorylation in vitro and increased CCL20, decreased IL-10, and increased number of dendritic cells in BAL fluid in vivo. Mutant SHP-1-transfected epithelial cells secreted higher levels of CCL20 and RANTES after exposure to oxidative stress. Furthermore, break of immune tolerance, as development of allergic airway inflammation, was observed in mev/+ mice after allergen exposure, which was suppressed by antioxidant N-acetylcystein. These data suggest that SHP-1 plays an important role in regulating oxidative stress. Thus increased intracellular oxidative stress and lack of SHP-1 in the presence of Th2-prone cellular activation may lead to the development of allergic airway inflammation.