Background: The surface expression of P-selectin on platelets contributes to the progression of inflammatory processes and thrombosis in atherothrombosis. In this study, we showed that the combination regimen of clopidogrel with aspirin could downregulate the P-selectin expression on platelets and the plasma concentration of C-reactive protein (CRP) in acute stage of atherosclerotic ischemic stroke. Methods: Patients with acute ischemic stroke (< 24 hours) were randomized for 7 days to combined regimen of clopidogrel and aspirin (n=24) or intravenous heparin with aspirin (n=28). We measured the changes of National Institute of Health Stroke Scale (NIHSS) scores, CRP concentration, and surface expressions of P-selectin on platelets during 7 days. Results: The combined regimen of clopidogrel and aspirin significantly reduced platelet P-selectin expression (93.6 +/- 16.6, p< 0.01) and plasma concentration of CRP (1.2 +/- 1.5 mg/dl, p< 0.01) after 7 days of stroke onset compared with the values (P-selectin; 115.5 +/- 20.7, CRP; 2.5 +/- 2.8 mg/dl) of initial 24 hr. Also, the clinical improvement, as measured by NIHSS score, was significant in the clopidogrel loading group at 7 days (6.2 +/- 5.5, p< 0.05) compared to the initial 24 hrs (10.1 +/- 7.6). Conclusion: Our results indicate that the combined regimen of clopidogrel and aspirin has beneficial effects on regulating platelet activation and inflammatory processes in acute atherosclerotic ischemic stroke. Thus, this combination regimen deserves further evaluation in clinical trial for the treatment of acute atherosclerotic ischemic stroke.