The effects of the lipid-lowering drug gemfibrozil on platelet reactivity at rest and during submaximal exercise were investigated in 10 patients with serum cholesterol levels greater than 270 mg/dl. No significant changes were observed in platelet reactivity at rest after gemfibrozil treatment. However, a marked decrease in platelet reactivity was seen in almost all patients treated with gemfibrozil during exercise. The adrenaline concentration necessary to induce secondary aggregation increased in eight patients during exercise after gemfibrozil and in two after placebo treatment. When adenosine diphosphatase (2 to 4 mumol/L) was used to induce aggregation, 5-hydroxytryptamine (serotonin) and thromboxane B2 secretion by platelets decreased by 35% and 67%, respectively, during exercise in patients treated with gemfibrozil. The area under the aggregation curve decreased by 28% during exercise after gemfibrozil. No significant changes occurred in these variables during exercise after placebo. Thus, gemfibrozil seems to have antiplatelet effects that might have importance in the prevention of acute complications of atherosclerosis in patients with hypercholesterolemia.