Arachidonate 15-lipoxygenase (LO)-1 has been implicated in allergic inflammation and asthma. The overall effect of 15-LO in allergic inflammation in vivo is, however, unclear. This study investigates systemic allergen sensitization and local allergic airway inflammation and remodeling in mice lacking the murine 12/15-LO, the ortholog to human 15-LO-1. Upon systemic sensitization with intraperitoneal ovalbumin, 12/15-LO-/- mice produced elevated levels of allergen-specific immunoglobulin E compared with wild-type (Wt) controls. However, when challenged with repeated aerosolized allergen, sensitized 12/15-LO-/- mice had an impaired development of airway allergic inflammation compared with Wt controls, as indicated by reduced bronchoalveolar lavage fluid leukocytes (eosinophils, lymphocytes, macrophages) and Th2 cytokines (IL-4, IL-5, IL-13), as well as tissue eosinophils. Allergen-induced airway epithelial proliferation was also significantly attenuated in 12/15-LO-/- mice, whereas goblet cell hyperplasia was unaffected. However, 12/15-LO-/- mice had significantly reduced luminal mucus secretions compared with Wt controls. The repeated allergen challenges resulted in a dramatic increase of alpha-smooth muscle actin-positive alveolar cells in the peripheral airways, a phenomenon that was significantly less developed in 12/15-LO-/- mice. In conclusion, our data suggest that 12/15-LO-/- mice, although having a fully developed systemic sensitization, did not establish a fully developed allergic airway inflammation and associated manifestations of central and peripheral airway remodeling. These data suggest that 12/15-LO-derived metabolites play an important pathophysiologic role in allergen-induced inflammation and remodeling. Hence, pharmacologic targeting of the human 15-LO-1 may represent an attractive therapeutic strategy to control inflammation and remodeling in asthma.