The extent of luminal involvement of atherosclerotic vascular disease and platelet reactivity portend subsequent cardiovascular events. This study was designed to determine whether platelet reactivity correlates with the extent of the territorial distribution of vascular disease. Blood was obtained from 130 patients who had known atherosclerotic vascular disease categorized as being in > or =1 of the following territories: coronary artery disease (CAD; n = 89), cerebrovascular disease (n = 36), and peripheral arterial disease (n = 61). Platelet reactivity, i.e., the activation of platelets in response to a low concentration of adenosine diphosphate (0.2 micromol/L), was measured using flow cytometry. Patients with vascular disease in >1 territory compared with those with disease in only 1 territory had greater platelet reactivity with respect to P-selectin expression (p = 0.01). The percentages of platelets expressing P-selectin (mean +/- SD) were 6.4 +/- 4.2 in patients who had involvement of 1 territory (n = 88), 10.0 +/- 6.8 in those who had involvement of 2 territories (n = 28), and 10.1 +/- 9.9 in those who had involvement of 3 territories (n = 14). Patients who had CAD and diabetes mellitus had greater P-selectin expression than did those who had CAD without diabetes (p <0.02 for interaction). Thus, platelet reactivity is greater in patients who have more extensive territorial distribution of atherosclerotic vascular disease and in those who have CAD and diabetes mellitus. Accordingly, patients who have more widely distributed vascular disease are likely to derive particular benefit from antiplatelet regimens that suppress platelet function to a greater extent.