Extracellular histones are major mediators of death in sepsis. This study shows that histones released during inflammation contribute to endothelial dysfunction, organ failure, and death in sepsis. Histones are cytotoxic to endothelial cells and can be targeted by antibodies or activated protein C (APC). In experiments, antibodies to histones reduced mortality in sepsis models, and APC reduced histone cytotoxicity. Histones were detected in the circulation of baboons challenged with E. coli, and their levels increased with the onset of renal dysfunction. APC cleaves histones and reduces their toxicity. Co-infusion of APC with E. coli or histones prevented lethality. Blockade of protein C activation exacerbated sepsis, which was reversed by histone antibodies. These findings suggest that extracellular histones are potential therapeutic targets for sepsis and other inflammatory diseases. The study also shows that APC can cleave histones in vitro and in vivo. Histones are toxic to endothelial cells, and APC reduces this toxicity by cleaving histones. Histones H3 and H4 are the main contributors to this toxicity. In vivo, APC co-infusion protected renal function in baboons challenged with E. coli. Histones were also found in septic patients, and APC treatment led to significant cleavage of H3. These results suggest that APC cleavage of extracellular histones is a new mechanism contributing to its beneficial effects in sepsis. In vivo, histones caused severe inflammatory responses, including neutrophil margination, vacuolated endothelium, intra-alveolar hemorrhage, and microthrombosis. Antibody to H4 protected mice from LPS, CLP, and TNF-induced lethality. Histone levels increased with the onset of acute renal failure, and H3 levels were reduced by H4 antibody treatment. These findings indicate that H4 plays a role in facilitating histone release. The study also shows that delay in treatment and the use of antibiotics are necessary to achieve therapeutic benefit with histone antibodies, possibly due to the functions of histones in innate immunity. Extracellular histones, mainly H3 and H4, appear to be both biomarkers of disease progression and therapeutic targets in sepsis and other inflammatory diseases. An effective histone blocking agent, such as the antibody described here, might prove therapeutic without the bleeding complications that can result from APC therapy. If effective, this approach is especially attractive in post-surgical patients or patients with sepsis following trauma who are currently excluded from APC therapeutic intervention.Extracellular histones are major mediators of death in sepsis. This study shows that histones released during inflammation contribute to endothelial dysfunction, organ failure, and death in sepsis. Histones are cytotoxic to endothelial cells and can be targeted by antibodies or activated protein C (APC). In experiments, antibodies to histones reduced mortality in sepsis models, and APC reduced histone cytotoxicity. Histones were detected in the circulation of baboons challenged with E. coli, and their levels increased with the onset of renal dysfunction. APC cleaves histones and reduces their toxicity. Co-infusion of APC with E. coli or histones prevented lethality. Blockade of protein C activation exacerbated sepsis, which was reversed by histone antibodies. These findings suggest that extracellular histones are potential therapeutic targets for sepsis and other inflammatory diseases. The study also shows that APC can cleave histones in vitro and in vivo. Histones are toxic to endothelial cells, and APC reduces this toxicity by cleaving histones. Histones H3 and H4 are the main contributors to this toxicity. In vivo, APC co-infusion protected renal function in baboons challenged with E. coli. Histones were also found in septic patients, and APC treatment led to significant cleavage of H3. These results suggest that APC cleavage of extracellular histones is a new mechanism contributing to its beneficial effects in sepsis. In vivo, histones caused severe inflammatory responses, including neutrophil margination, vacuolated endothelium, intra-alveolar hemorrhage, and microthrombosis. Antibody to H4 protected mice from LPS, CLP, and TNF-induced lethality. Histone levels increased with the onset of acute renal failure, and H3 levels were reduced by H4 antibody treatment. These findings indicate that H4 plays a role in facilitating histone release. The study also shows that delay in treatment and the use of antibiotics are necessary to achieve therapeutic benefit with histone antibodies, possibly due to the functions of histones in innate immunity. Extracellular histones, mainly H3 and H4, appear to be both biomarkers of disease progression and therapeutic targets in sepsis and other inflammatory diseases. An effective histone blocking agent, such as the antibody described here, might prove therapeutic without the bleeding complications that can result from APC therapy. If effective, this approach is especially attractive in post-surgical patients or patients with sepsis following trauma who are currently excluded from APC therapeutic intervention.