Separate mechanisms of action account for the effects of platelets on maintenance of vascular endothelium and on bleeding from mechanically injured vessels. Circulating platelets in excess of 50,000/mm³ are needed in thrombocytopenic dogs to consistently reduce their bleeding time to normal levels. Significant reduction of red cell diapedesis into the lymph, an index of endothelial damage, was observed following transfusions of small amounts of platelets in the same animal model whether or not the platelet count was increased. The known dependence of the bleeding time on “hemostatic plug” formation suggests that higher levels of circulating platelets are needed for its adequate formation, while small numbers of functional platelets may be needed to support the integrity of vascular endothelium. Since endothelial changes appear to account for initiating spontaneous bleeding and lack of hemostatic plug formation for its continuation, various programs of platelet replacement may be needed by thrombocytopenic individuals requiring prophylactic or therapeutic platelet transfusions.