Orthostatic stress causes significant plasma shift and raises transmural pressure in lower extremities, resulting in an increase in endothelial activation and plasma proteins concentrations, possibly including coagulation factors. This may lead to activation of the coagulation system during standing. To test this hypothesis, we recruited 18 healthy volunteers (9 females and 9 males; mean age: 25±1.2 years; body mass index: 21.7±0.5 kg/m2). Hemodynamics, plasma shift (extrapolated from sequential hematocrit concentration), plasma proteins, and coagulation tests, including procoagulants; fibrinogen, factor V, and factor VIII activity; prothrombin fragments 1 and 2; and endothelial activation–related factors (tissue factor and von Willebrand factor), as well as protein C global pathway, were determined at rest supine and at 15 minutes, 30 minutes, and 60 minutes of still standing. Thirty minutes of standing caused a decrease in plasma volume by 12.0±0.5% and an increase in plasma protein by 13.0±0.7%. Fibrinogen, factor V, and factor VIII activity rose by 12.0±1.2%, 13.0±1.0%, and 40.0±6.0% (P<0.002 for all), respectively. Prothrombin fragments 1 and 2 were elevated by 150.0±30.0%. Tissue factor and von Willebrand factor increased by 30.0±9.0% and 17.4±51.0% (P<0.02 for both), respectively. However, protein C assay results decreased from 0.95±0.20 to 0.83±0.16 (P<0.001). We hereby introduce a novel physiological mechanism, “orthostatic procoagulation,” that should be considered during coagulation tests. Furthermore, it could be extrapolated to the pathophysiology of stasis and venous thromboembolism.