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 affects APC 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 in PC^+/− 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.