The retinoid-related orphan receptor {ROR), a member of the ROR subfamily of nuclear receptors, has been implicated in the control of a number of physiological processes, including the regulation of several immune functions. To study the potential role of ROR in the regulation of innate immune responses in vivo, we analyzed the induction of airway inflammation in response to lipopolysaccharide (LPS) challenge in wild type and staggerer (ROR^sg/sg) mice, a natural mutant strain lacking ROR expression. Examination of hematoxylin and eosin stained lung sections showed that ROR^sg/sg mice displayed a higher degree of LPS-induced inflammation than wild type mice. Bronchoalveolar lavage (BAL) was performed at 3, 16, and 24 h after LPS exposure to monitor the increase in inflammatory cells and the level of several cyto/chemokines. The increased susceptibility of ROR^sg/sg mice to LPS-induced airway inflammation correlated with a higher number of total cells and neutrophils in BAL fluids from LPS-treated ROR^sg/sg mice compared to those from LPS-treated wild type mice. In addition, interleukin-1 (IL-1), interleukin-6 (IL-6), and macrophage inflammatory protein-2 (MIP-2) were appreciably more elevated in BAL fluids from LPS-treated ROR^sg/sg mice compared to those from LPS-treated wild type mice. The enhanced susceptibility of ROR^sg/sg mice appeared not to be due to a repression of inhibitor kappa B-alpha (IB) expression. Our observations indicate that ROR^sg/sg mice are more susceptible to LPS-induced airway inflammation and are in agreement with the hypothesis that ROR functions as a negative regulator of LPS-induced inflammatory responses.