Systemic inflammation remains a major cause of morbidity and mortality in the United States， across many disease processes. One classic murine model to study this syndrome is lipopolysaccharide (LPS)-induced Toll-like receptor 4 (TLR4)-dependent systemic inflammation. Although most studies have focused on inflammatory cell TLR4 responses， parenchymal cells also express TLR4. Our objective was to define the in vivo role of parenchymal- versus marrow-derived cell activation via TLR4 during LPS-induced inflammation. Mice bearing TLR4 on parenchymal cells only， marrow-derived cells only， both， or neither were generated using bone marrow transplantation. Mortality occurred only in mice that had TLR4 expression on their parenchymal cells. Before onset， virtually all major plasma cytokines and blood neutrophil responses were related to marrow-derived cell activation via TLR4. The only cytokine predictive of oncoming systemic inflammation was the chemokine monocyte chemoattractant protein-1. Late blood neutrophil responses were related to the presence of TLR4 on either parenchymal or marrow cells， whereas plasma cytokine elevations late in LPS-induced systemic inflammation were dependent on mice having TLR4 in both cell compartments. Parenchymal cell activation via TLR4 is a key component of LPS-induced systemic inflammation and mortality， although most plasma cytokine levels and blood neutrophil responses were not key components. Given its unique role， future studies into monocyte chemoattractant protein-1's exact role during systemic inflammation are warranted.