Aspirin (acetylsalicylic acid, ASA), which is recommended for primary and secondary prevention in diabetes mellitus (DM), has been shown to have a lower antiplatelet activity in diabetic patients. We conducted a crossover designed observational study to evaluate whether there is an association between the parameters relevant to metabolic control of diabetes and platelet sensitivity to aspirin in type 2 diabetic patients. Platelets' ability to adhere and aggregate was monitored with the use of platelet function analyser (PFA-100 collagen/epinephrine closure time, CT(CEPI) or collagen/ADP closure time, CT(CADP)), classical turbidimetric aggregometry and whole blood electrical aggregometry (WBEA), using collagen (WBEA(coll)), ADP (WBEA(ADP)) and arachidonic acid (WBEA(AA)) as platelet agonists, in 48 control healthy volunteers (mean age+/-S.D., 49+/-9 years) and 31 type 2 DM patients (50+/-9 years; HbA(1c) 9.4+/-1.6%). In majority of control subjects (69%) and minority of diabetic patients (29%, p=0.0006), the use of 150 mg aspirin daily for 1 week significantly reduced platelet adhesiveness and reactivity (by 14.1% in diabetes vs. 78.6% in control, p(np)=0.0035, as expressed by the relative changes in CT(CEPI)). Aspirin reduced WBEA(coll) and WBEA(AA) to a lesser extent in diabetic patients (by 2.1% vs. 8.3% in controls, p(np)=0.0397, and by 97.3+/-12.8% vs. 100% in controls, p(np)=0.0383, respectively), which corresponded to ASA-mediated decreased aggregation in platelet-rich plasma (PRP, r(S)=0.45 and r(S)=0.78 for collagen- or arachidonate-agonized platelets, p<0.01 or lower). The maximal inhibition of platelet aggregation was lower and IC(50) higher in diabetic compared to control subjects, both in the presence of arachidonic acid (71% vs. 39%, p(np)0.0001; 0.5 microg/ml vs. 1.3 microg/ml, p<0.0001) and collagen (52% vs. 35%, p<0.0004; 1.6 microg/ml vs. 2.1 microg/ml, p<0.01). The reduced response of platelets from diabetic subjects to aspirin was associated with a higher level of HbA(1c), lower concentration of HDL-cholesterol and a higher total cholesterol concentration. Overall, there is evidence that reduced platelets response to aspirin may occur more often in diabetic patients. Poor metabolic control may play a role in the reduced platelet sensitivity to aspirin in DM patients. Thus, our findings strongly support the requirements for an excellent near-normal metabolic control and may suggest a need for alternative ASA dosing schedules in DM patients.