Pharmacologic infusion of activated protein C (APC) improves survival in severe sepsis, and platelet factor 4 (PF4) accelerates APC generation in a primate thrombin-infusion model. We now tested whether endogenous platelet PF4 content affectsAPC generation. Mice completely deficient in PF4 (mPF4 -/-) had impaired APC generation and survival after thrombin infusion, similar to the impairment seen in heterozygote protein C-deficient (PC+/-) mice. Transgenic mice overexpressing human PF4 (hPF4 +) had increased plasma APC generation. Overexpression of platelet PF4 compensated for the defect seen inPC+/- mice. In both a thrombin and a lipopolysaccharide (LPS) survival model, hPF4+ and PC +/-/hPF4+ mice had improved survival. Further, infusion of hPF4+ platelets improved survival of wild-type mice after an LPS challenge. These studies suggest that endogenous PF4 release may have biologic consequences for APC generation and survival in clinical sepsis. Infusions of PF4-rich platelets may be an effective strategy to improve outcome in this setting.