The concept of restoring hemostasis by down-tuning anticoagulant pathways holds the promise of treating all forms of hemophilia. Here we report preclinical efficacy and safety data for SerpinPC, a covalent inhibitor of activated protein C (APC). APC is a serine protease that degrades the enzyme complex that produces thrombin, and its inhibition allows more thrombin to be produced during the initiation stage of hemostasis. In a hemophilia A (HA) mouse tail clip model, SerpinPC treatment reduced blood loss in a dose- and time-dependent manner to the levels of wild-type (WT) mice. SerpinPC was able to treat active bleeds in HA mice, and prevented spontaneous internal bleeding when given prophylactically. SerpinPC treatment was not associated with an increased inflammatory response and was well tolerated at high doses in WT animals. SerpinPC is currently being evaluated in persons with severe hemophilia.