In a series of in vitro studies, both the soluble (plasmatic) coagulation system and the cellular (platelet-mediated) aspect of human blood coagulation were extremely sensitive to relatively minor increases in H ion concentration. All studies became abnormal at pH 6.8. At pH 6.4 assays of the intrinsic and extrinsic coagulation systems, the polymerization of fibrinogen and assay of the availability of platelet phospholipid (platelet factor 3) were twice prolonged over control values. Platelet aggregation was reduced by more than 50%. At pH 5.4 in vitro, platelet aggregation and plasma coagulation were virtually abolished. Previously formed platelet aggregates disaggregated at a slightly acid pH. Pepsin further enhanced platelet disaggregation. Because gastric acidity is normally 2-4 orders of magnitude greater than that which abolishes platelet aggregation and plasma clotting in vitro, and pepsin is present in abundance, attention is called to the probable antihemostatic effect of HCl and pepsin in the upper gastrointestinal tract. This in vitro study may provide a rationale for meticulous regulation of intragastric pH in an effort to control upper gastrointestinal hemorrhage.