Inhibitory antibodies to factors VIII or IX represent a serious complication for hemophilia patients. Treatment involves products that bypass the intrinsic pathway and promote thrombin generation. Direct infusion of factor Xa should also restore hemostasis; however, it has a short half-life in plasma and could activate systemic coagulation in an uncontrolled fashion. Here we show that factor Xa mutants with zymogen-like properties (FXa(I16L) and FXa(V17A)) circumvent these limitations. In the absence of factor Va, the FXa variants are poor enzymes for a range of physiological ligands and are resistant to inactivation by antithrombin III and tissue factor pathway inhibitor. Notably, assembly of FXa(I16L) and FXa(V17A) on activated platelets with factor Va to form prothrombinase completely restores biologic activity. In hemophilic plasma, FXa(I16L) and FXa(V17A) have prolonged half-lives compared with wild-type factor Xa (approximately 60 minutes vs approximately 1 minute) and promote robust thrombin generation that bypasses the intrinsic pathway. The variants require factor Va generated in situ for procoagulant function, and cofactor inactivation by the protein C pathway regulates their activity. The efficacy, extended half-life, and mechanism of action suggest that novel zymogen-like forms of factor Xa might prove useful as new therapeutic procoagulants to treat deficiencies upstream of the common pathway.