Recent studies have shown that endothelial protein C receptor (EPCR) polymorphisms and soluble EPCR levels are associated with thrombotic diseases. It is unknown whether membrane EPCR (mEPCR) heterozygosity and/or physiologically elevated sEPCR levels directly impact the hemostatic balance and the outcome of endotoxemia. In these studies, thrombin infusion experiments revealed that EPCR heterozygosity (Procr+/-) impaired protein C activation by approximately 30%. Infusion of factor Xa with phospholipid demonstrated that the Procr+/- genotype increased the coagulant response relative to wild-type mice. Challenge of the Procr+/- mice with lipopolysaccharide (LPS) did not significantly exaggerate their response compared with wild-type mice. We also generated mice in which one allele of full-length EPCR was replaced by sEPCR (Procrs/+). Compared with Procr+/- mice, Procrs/+ mice had 5-fold higher sEPCR and similar mEPCR levels. Procr+/- and Procrs/+ mice generated similar levels of activated protein C (APC) upon thrombin infusion. They also exhibited a similar coagulant response upon factor Xa/phospholipid infusion. Only supraphysiologic levels of sEPCR could influence protein C activation and exaggerate the coagulant response. In conclusion, mEPCR, but not physiologically elevated sEPCR, regulated protein C activation. Procr heterozygosity results in a mild increase of thrombosis tendency and little influence on the response to endotoxin.