The inflammatory phenotype of genetically modified mice is complex, and the role of Gram-negative lipopolysaccharide (LPS) in acute inflammation induced by surgical cannulation trauma, alone or in combination with hemorrhage and resuscitation ("hemorrhagic shock"), is both complex and controversial. We sought to determine if a mathematical model of acute inflammation could elucidate both the phenotype of CD14-deficient (CD14 -/-) mice-following LPS, cannulation, or hemorrhagic shock- and the role of LPS in trauma/hemorrhage-induced inflammation. A mathematical model of inflammation initially calibrated in wild-type (C57BI/6) mice subjected to LPS, cannulation, and hemorrhagic shock was recalibrated in CD14-/- mice subjected to the same insults, yielding an ensemble of models that suggested specific differences at the cellular and molecular levels (for example, 43-fold lower activation of leukocytes by LPS). The CD14-/--specific model ensemble could account for complex changes in inflammatory analytes in these mice following LPS treatment. Model prediction of similar organ damage in CD14-/- and wild-type mice subjected to cannulation alone or with hemorrhagic shock was verified in vivo (similar ALT levels). These studies suggest that LPS-CD14 responses do not cause inflammation in surgical trauma/hemorrhagic shock and demonstrate a novel use of combined in silico and in vivo methods to elucidate the complex inflammatory phenotype of genetically modified animals.