Diabetes mellitus is associated with a high incidence of cardiovascular diseases not directly attributable to hyperlipidemia, smoking, or hypertension, but which in part may be explained by an enhanced tendency to thrombosis due to increased platelet activity. The aim of this study was to evaluate platelet function and compare the effectiveness of the antiplatelet drug aspirin on platelet aggregation in diabetic and nondiabetic subjects. Platelet aggregation and composition were examined in 20 male Insulin-dependent diabetes mellitus (IDDM) patients and 20 nondiabetic control subjects matched for age and body mass Index. All were normotensive with serum total cholesterol P < 0.05). Serum thromboxane B2 and ex vivo aggregation of platelets In response to two doses of the agonists collagen and platelet-activating factor (PAF) were similar to nondiabetic subjects. However, after taking 100 mg/day aspirin for 5 days, platelet aggregation to collagen was reduced by 76% in control subjects compared to 56% in IDDM patients (P < 0.001). Aspirin treatment also reduced the slope of the aggregation curve and increased the lag time (the period between the addition of collagen and the start of irreversible aggregation) significantly more in control than In diabetic platelets. This difference in platelet aggregation could not be attributed to differences in platelet serotonin or thromboxane A2 secretion, the latter being almost completely suppressed by aspirin in each group. Platelet aggregation to PAF was similar in both groups and was not affected by aspirin. IDDM patients had a significantly higher percentage of linoleic acid but lower percentage of ω-3 fatty acids in plasma and platelet phospholipids. The phospholipid-cholesterol ratio and membrane fluidity were not altered in diabetic platelets. These results suggest that platelets from IDDM patients are resistant to the effect of aspirin by mechanisms independent of both the cyclooxygenase and PAF pathways of aggregation.