Vigorous exercise transiently increases the risk of primary cardiac arrest. Strenuous, acute exercise can also increase the release of plasma epinephrine. Previous investigations have indicated that epinephrine can potentiate platelet activation by activating platelet alpha2-adrenoceptors. This study investigated how strenuous, acute exercise affects alpha2-adrenergic agonist-potentiated platelet activation by closely examining 15 sedentary men who exercised strenuously on a bicycle ergometer. Before and immediately after exercise, platelet adhesiveness on fibrinogen-coated surfaces, [Ca2+]i in platelets, the number and affinity of alpha2-adrenergic sites on the platelet surface, and plasma catecholamine levels were determined. The results of this study can be summarized as follows: (1) The affinity of alpha2-adrenergic receptors on platelets decreases while the maximal binding number significantly increases after strenuous exercise, thereby correlating with the rise in plasma catecholamine levels. (2) Basal, clonidine-treated, ADP-treated, and clonidine plus ADP-treated adhesiveness and [Ca2+]i in platelets increased after strenuous exercise. (3) Strenuous exercise is associated with higher percentages of ADP- and clonidine plus ADP-enhanced platelet adhesiveness and [Ca2+]i than at rest. (4) The synergistic effects of clonidine on ADP-enhanced platelet adhesiveness and [Ca2+]i after strenuous exercise are much greater than those at rest. Therefore, we conclude that strenuous, acute exercise enhances platelet activation, possibly by altering the performance of platelet alpha2-adrenergic receptors, facilitating the ability of ADP-activated fibrinogen receptors, and enhancing fibrinogen binding to platelet fibrinogen receptors.