Objective: To assess whether adding clopidogrel to acetylsalicylic acid (ASA) has a long-term protective vascular effect in patients with lacunar stroke while taking ASA. Methods: Post hoc analysis of 838 patients with ASA failure and recent lacunar stroke from the Secondary Prevention of Small Subcortical Strokes Trial (SPS3) cohort randomly allocated to aspirin (325 mg/day) and clopidogrel (75 mg/day) or placebo. Primary efficacy outcome was stroke recurrence (ischemic and intracranial hemorrhage) and main safety outcome was major extracranial hemorrhage. Patients were followed for a mean period of 3.5 years. Results: The ASA failure group had a significantly higher risk of vascular events including ischemic stroke when compared with the non-ASA failure group (n = 2,151) in SPS3 (p = 0.03). Mean age was 65.6 years and 65% were men. The risk of recurrent stroke was not reduced in the dual antiplatelet group, 3.1% per year, compared to the aspirin-only group, 3.3% per year (hazard ratio [HR] 0.91; 95% confidence interval [CI] 0.61-1.37). There was also no difference between groups for ischemic stroke (HR 0.90; 95% CI 0.59-1.38). The risk of gastrointestinal bleeding was higher in the dual antiplatelet group (HR 2.7; 95% CI 1.1-6.9); however, the risk of intracranial hemorrhage was not different. Conclusions: In patients with a recent lacunar stroke while taking ASA, the addition of clopidogrel did not result in reduction of vascular events vs continuing ASA only. Classification of evidence: This study provides Class I evidence that for patients with recent lacunar stroke while taking ASA, adding clopidogrel as compared to continuing ASA alone does not reduce the risk of recurrent stroke.