Men have significantly more atherosclerotic disease than women. Platelet-mediated thrombosis plays a role in the initiation of myocardial infarction and stroke. Citrated whole blood from male and female donors was perfused through an annular system over everted human umbilical artery segments. Comparisons were made between platelet adherence and thrombus formation on subendothelium, platelet aggregation in citrated whole blood, hematologic variables, and the bleeding time. Platelet spreading and adherence were approximately 22% greater with male blood (P < 0.001), whereas thrombus formation on subendothelium and collagen- and arachidonic acid-induced platelet aggregation did not show sex-related differences. Platelet aggregation with adenosine diphosphate was greater in women, related to their lower hematocrit values. By contrast, in women hematocrit values showed a slight but significant positive correlation with platelet adherence on subendothelium. Fibrinogen was significantly correlated with collagen- and adenosine-diphosphate-induced platelet aggregation and with platelet adherence, spreading, and thrombus formation on subendothelium. The mean bleeding time was slightly longer in women than in men (P = 0.118). Platelet aggregation was not associated with the bleeding time except for collagen-induced platelet aggregation in males; the latter was significantly correlated with platelet adherence and spreading in both sexes, while arachidonic acid-induced platelet aggregation predicted platelet adherence and spreading in males. Male blood shows enhanced primary hemostatic activity; this may predispose men to atherosclerosis.