Increased platelet-leukocyte-aggregate (PLA) formation has been reported in acute coronary syndromes (ACS) and during cardiopulmonary bypass, and PLA formation has been acknowledged as a possible target for antiplatelet therapy in ACS and coronary interventions. It has also been suggested as a monitoring tool for risk stratification parameters. In a controlled study design as well as under clinical conditions we investigated the effect of antiplatelet agents by flow cytometric measurement of PLA formation. We were able to demonstrate considerable reduction in PLA formation under experimental and clinical clopidogrel therapy alone or in combination with aspirin. In healthy volunteers the percentage of monocyte-PLAs decreased significantly to 55 to 75% of the baseline under clopidogrel, depending on the type and concentration of the activating agent. In patients with severe peripheral artery disease, formation of monocyte-PLAs at baseline and after stimulation with thrombin receptor activating peptide (TRAP) or adenosine diphosphate (ADP) was significantly lower under combined therapy when compared with patients under aspirin alone or without antiplatelet treatment. Flow cytometric measurement of PLA formation appears to be well suited for dose response of antiplatelet agents in healthy volunteers and a valuable tool in establishing the clinical significance of circulating PLAs. It may also be a qualified method to monitor platelet function in long-term treatment with antiplatelet agents that interfere with the degranulation process. It is not suited for acute situations.