Despite of a plenty of studies on ER stress in various inflammatory diseases, there is scarce information on ER stress in bronchial asthma. In this study, we aimed to elucidate the role of ER stress in the pathogenesis of bronchial asthma using mice sensitized with OVA and LPS and then challenged with OVA (OVALPS-OVA mice) as well as OVA-sensitized and-challenged mice (OVA-OVA mice). The OVALPS-OVA mice showed that the expression of ER stress markers and the protein levels of unfolded-protein response (UPR)-related markers in lung tissues were significantly increased after OVA challenge. Moreover, we found that ER stress markers in peripheral blood mononuclear cells from human asthmatics were dramatically increased compared with those from healthy controls. In OVALPS-OVA mice, 4-phenylbutyric acid (4-PBA), a chemical chaperone significantly reduced the increases in ER stress, inflammatory cytokines, DCs infiltration with TLR4 expression, airway inflammation, and bronchial hyperresponsiveness, while it further enhanced the increase of IL-10. Additionally, the established asthmatic features of OVA-OVA mice were substantially attenuated by 4-PBA administered after completion of OVA challenge. These results indicate that ER stress may be implicated in the pathogenesis of bronchial asthma, at least in part, through modulation of innate immunity and regulatory T cell response.