Objective: Endotoxins represent one of the most potent classes of microbial immunoactive components that can cause pulmonary inflammation. The aim of this study was to compare the inflammatory potency of two types of Neisseria meningitidis endotoxins (lipooligosaccharides) in lungs: wild type (hexaacylated, LOS^wt) and mutant type (pentaacylated, LOS^msbB), and to determine the importance of MD-2 in endotoxin responses in lungs in vivo. Methods: Endotoxin normoresponsive mice (BALB/c) were exposed to selected doses of penta- and hexaacylated LOS by nasal aspiration. Cellular and cytokine/chemokine inflammatory responses in bronchoalveolar lavage were measured at 1, 4, 8, 16, 24, and 48 h time points. MD-2 null mice were exposed to one dose of hexaacylated LOS and inflammatory responses were measured after 4 and 24 h. Results: Inhalation of hexaacylated resulted in strong inflammatory responses while pentaacylated LOS was much less potent in inducing increases of neutrophils, TNF-, MIP-1, IL-6, G-CSF, and IL-1 concentration in bronchoalveolar lavage. Similar kinetics of inflammatory responses in lungs was found in both types of endotoxin exposures. Inhalation of hexaacylated LOS in MD-2 null mice resulted in significantly lower numbers of neutrophils in bronchoalveolar lavage than in normoresponsive mice. Conclusion: Markedly lower inflammatory potency of pentaacylated LOS was observed in comparison with hexaacylated LOS. Hyporesponsiveness in MD-2 null mice after nasal aspiration of wild type LOS indicate its essential role in airway responsiveness to endotoxin.