Rationale: Nuclear receptors play a critical role in the regulation of inflammation, thus representing attractive targets for the treatment of asthma. Objective: In this study, we assess the potential regulatory function of retinoid-related orphan receptor α (RORα) in the adaptive immune response using ovalbumin (OVA)-induced airway inflammation as a model. Methods: Allergen-induced inflammation was compared between wild-type (WT) and staggerer (RORαsg/sg) mice, a natural mutant strain that is deficient in RORα expression. Measurements and Main Results: Despite robust increases in OVA-specific IgE, RORαsg/sg mice developed significantly less pulmonary inflammation, mucous cell hyperplasia, and eosinophilia compared with similarly treated WT animals. Induction of Th2 cytokines, including interleukin (IL)-4, IL-5, and IL-13, was also significantly less in RORαsg/sg mice. Microarray analysis using lung RNA showed increased expression of many genes, previously implicated in inflammation, in OVA-treated WT mice. These include mucin Muc5b, the chloride channel calcium-activated 3 (Clca3), macrophage inflammatory protein (MIP) 1α and 1β, eotaxin-2, serum amyloid A3 (Saa3), and insulin-like growth factor 1 (Igf1). These genes were induced to a greater extent in OVA-treated WT mice relative to RORαsg/sg mice. Conclusions: Our study demonstrates that mice deficient in RORα exhibit an attenuated allergic inflammatory response, indicating that RORα plays a critical role in the development of Th2-driven allergic lung inflammation in mice, and suggests that this nuclear receptor should be further evaluated as a potential asthma target.