Background and purpose: Active smokers with myocardial infarction were shown to have enhanced benefit with clopidogrel compared with aspirin. Whether this "paradox" exists in ischemic stroke patients is unknown. We aimed to investigate whether smoking status has a differential impact on the efficacy of clopidogrel vs. aspirin in patients with non-cardioembolic strokes. Methods: This single-center study retrospectively assessed 1792 non-cardioembolic ischemic stroke patients discharged from January 2013 to October 2014, and followed for 12 months. Patients were categorized as current-smokers and never-smokers. Primary outcome was a composite of secondary ischemic stroke, myocardial infarction and all-cause death. Secondary outcome was secondary ischemic stroke. Results: 1066 patients were current-smokers and 726 were never-smokers. Compared with never -smokers, current -smokers had significantly higher rates of ischemic stroke (4.3% vs. 1.2%; adjusted OR: 3.60, 95%Cl: 1.50-8.64, p = 0.004). Regarding the primary outcome, among smokers, rates showed a lower trend in clopidogrel vs. aspirin groups (3.7% vs. 6.4%; adjusted OR 0.57, 95%Cl: 0.31-1.07, p = 0.08), but no difference among never smokers (2.1% vs. 1.0%; adjusted OR: 1.67, 95%Cl: 0.47-5.89, p = 0.42). Similarly, among smokers, trending lower rates for recurrent ischemic stroke were observed in clopidogrel vs. aspirin group (3.1% vs. 5.0%; adjusted OR: 0.60, 95%Cl: 0.31-1.18, p = 0.14); but no difference between the two groups among never -smokers (1.7% vs. 1.0%; adjusted OR 1.36, 95%Cl: 0.36-5.52, p = 0.65). Conclusions: Smoking is a major risk factor for recurrent stroke in our retrospective non-cardioembolic ischemic stroke cohort. Active -smokers trend toward better cardiovascular outcomes when on clopidogrel. This finding needs to be confirmed in a prospective cohort. (C) 2016 Published by Elsevier B.V.