The platelets of many patients with diabetes mellitus are abnormally sensitive to the effects of aggregatory agents in vitro. It has been proposed that this abnormal platelet function may play a role in the pathogenesis of vascular disease in diabetic subjects. We have investigated the effects of six weeks of treatment with the sulfonylurea agents gliclazide and glyburide on platelet aggregation in 10 noninsulin-dependent diabetic subjects. During treatment with diet alone, the platelets of these patients were abnormally sensitive to aggregation in response to 1 microM of adenosine diphosphate, as compared with those in normal controls. Treatment with both drugs normalized ADP-induced aggregation in these patients. Treatment with glyburide significantly reduced aggregation in response to 10 microM of epinephrine and collagen at 750 microgram/ml. The alteration in platelet function did not correlate with the improvement in plasma glucose concentration, thus suggesting that this may be an effect of the drug. Although one must be cautious in extrapolating these in vitro findings to the clinical situation, this alteration in platelet aggregatory function may be of importance in the prevention of vascular disease in diabetic subjects.