PhoP is part of a two-component regulatory system, which we have previously demonstrated in Neisseria meningitidis and shown to be an important regulator of virulence in an in vivo model. The phoP mutant clearly induced cross-species reactive antibodies and lacks the obvious toxic effects of the wild-type strain. In the current study, we demonstrate distinct differences between the wild-type and mutant strains in an in vitro model of toxicity. At concentrations likely to be present early in an infection, the mutant was more efficient at stimulating an inflammatory response than the wild-type. However, at the concentrations likely to be found at the site of a fulminant infection, the mutant showed significantly weaker ability to stimulate the release of pro-inflammatory cytokines and the production of reactive oxygen and nitrogen intermediates. SDS-PAGE analysis of the isolated LOS from the wild-type and mutant showed a difference in the level of expression of two major species of LOS, a finding which was supported by preliminary MALDI-TOF analysis. These results suggest that the altered toxicity of the mutant may be due to the increased expression of a conformationally altered LOS species, which shows less affinity and avidity for the cellular receptors responsible for the inflammatory response to endotoxin.