Introduction: Platelet activation is an important mediator in acute thrombosis as well as systemic inflammation. Therefore, modulating P2Y12 receptor, a well-known platelet activation pathway, may influence inflammation process. Clopidogrel, a prototype P2Y12 receptor antagonist, is reported to decrease neutrophil infiltration and decrease inflammation. Hypothesis: The aim of this study is to evaluate whether clopidogrel use may decrease the risk of aspiration pneumonia, a common infection, in patients with acute ischemic stroke. Methods: A consecutive patients with acute ischemic stroke (within 7 days after onset) were screened between March 2010 and December 2015, and a total of 1,578 patients were included for the analysis. Patients were categorized into two groups (clopidogrel user vs. non-user), and the clinical characteristics and the risk of aspiration pneumonia were compared in two groups. Results: Among the included patients (mean age, 67.6 years; men, 60.7%), 642 (40.7%) were clopidogrel user, and 132 (8.2%) patients had aspiration pneumonia. The proportion of patients with aspiration pneumonia was significantly higher in clopidogrel non-user (9.9%) compared to clopidogrel user (6.1%), (P = 0.006). Moreover, clopidogrel users had lower proportion of ICU care (12.8 % vs. 38.7 %, P =0.03) and had less chances of having sepsis [defined as quick SOFA (sepsis related organ failure) score of 2 and more) ( 15.4 % vs. 32.4 %, P= 0.047) compared with clopidogrel non-users. The patients with aspiration pneumonia were more likely to have atrial fibrillation, diabetes mellitus, and higher initial NIHSS. On multivariate analysis with an application of inverse probability of treatment weighting based on a propensity score of clopidogrel use, clopidogrel users had lower risk of aspiration pneumonia [Odds ratio (95% confidence interval); 0.747(0.573-0.974), P = 0.007]. Conclusions: This study suggested that clopidogrel users had lower risk of aspiration pneumonia and less severe infection following acute ischemic stroke. This suggests that clopidogrel may decrease the chances of infection, especially aspiration pneumonia, after stroke.