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Summary. Background: Activated protein C (APC) is known to protect animals from sepsis. Endogenous protein C is important in protection. It is unknown whether the cytoprotective or anticoagulant properties of protein C (PC) are responsible for the protective effect of endogenous PC. Objective: To determine if signaling by endogenous activated protein C contributes to survival in sepsis. Methods: We used an immunochemical approach to either block all of the known activities of protein C using mAb MPC1609 or, alternatively, selectively block the anticoagulant activity of activated protein C while sparing some of its cytoprotective activities using mAb MAPC1591. Results: MPC1609 blocked APC binding to endothelium whereas MAPC1591 enhanced binding. MPC1609 prevented APC protection of endothelial barrier function whereas MAPC1591 did not. Injection of MPC1609, but not MAPC1591, with a sublethal dose of lipopolysaccharide (LPS) caused lethality. At 18 h, the mice injected with MPC1609 plus LPS had much higher interleukin-6 (IL-6) levels than mice injected with LPS alone or LPS plus MPC1591. In these mice treated with LPS plus MPC1609, higher blood urea nitrogen (BUN) and creatinine levels suggested that an acute renal failure might contribute to a slow clearance of IL-6. Conclusions: These studies demonstrate for the first time that cytoprotective activities of APC, and not the anticoagulant activity, is required for protection in this sepsis model. Similar anti-human antibodies may prove useful in clinical conditions such as trauma and hemophilia where cytoprotection is desirable, but the anticoagulant activity of endogenous activated protein C may contribute to bleeding.