Percutaneous coronary intervention (PCI) in patients presenting with acute coronary syndrome (ACS) is associated with increased risk of thrombotic complications. ACS enhances platelet activation; whether pretreatment with clopidogrel is sufficient to suppress platelet function in patients with ACS is not known. This study assessed platelet function in patients with and without ACS prior to PCI and after pretreatment with a single dose of 600 mg clopidogrel. Blood samples of 402 patients prior to PCI with (n = 119) or without (n = 283) ACS were collected at least 2 h after 600 mg clopidogrel administration. Maximal platelet aggregation in response to ADP (5 and 20 micromol/l), collagen (4 microg/ml) and TRAP (25 micromol/l) was measured with optical aggregometry. Surface expression of glycoprotein IIb/IIIa and P-selectin was assessed with flow cytometry at baseline and after stimulation with 5 and 20 micromol/l ADP. Agonist-induced platelet aggregation did not differ significantly between patients with and without ACS (P > or = 0.15). Parameters of platelet activation (glycoprotein IIb/IIIa and P-selectin surface expression) were significantly higher in ACS patients at baseline and after 5 and 20 micromol/l ADP stimulation (P < 0.0001). Patients with ACS continue to exhibit increased platelet activation after pretreatment with 600 mg clopidogrel. This finding supports the need for additional platelet function inhibition during PCI in patients with ACS.