Recently, our laboratory showed that platelets, like leukocytes, roll on activated endothelium expressing P-selectin, thus suggesting a role for P-selectin in hemostasis (Frenette et al, Proc Natl Acad Sci USA 92:7450, 1995). We report here that the P-selectin–deficient mice show a 40% prolongation of the bleeding time on amputation of the tip of the tail. Moreover, defective hemostasis was observed in a local Shwartzman-like reaction induced by skin injections of lipo-polysaccharide followed by tumor necrosis factor-α in the P-selectin–deficient mice. The hemorrhagic lesions, quantitated both macroscopicatly and microscopically, were twofold larger in the P-selectin–deficient mice. This was also confirmed by measuring the radioactivity in the skin using chromium-labeled red blood cells. Therefore, it is evident that P-selectin plays a role in hemostasis as suggested by its support of platelet rolling.