Lipopolysaccharide elicits a vigorous inflammatory response and has been linked to the progression of asthma and other forms of airway disease. An improved understanding of the innate immune response to lipopolysaccharide should lead to novel therapies to treat these diseases. Towards this end, we challenged 32 recombinant inbred (RI) strains of (C57BL/6J X DBA/2J) [BXD] mice with aerosolized lipopolysaccharide and compared their biological responses by assaying concentrations of tumor necrosis factor-α and polymorphonuclear cells in the lavage fluid. The biological responses of these RI strains ranged from less than the low-responder parental strain C57BL/6J to higher than the high-responder parental strain, DBA/2J. One RI strain was essentially unresponsive to lipopolysaccharide. Phenotypic analysis of F2 offspring from this unresponsive strain suggested these mice have a recessive mutation in a single, unidentified gene.