BACKGROUND: The prognostic value of occurrence of ischemic stroke in a patient despite aspirin treatment (aspirin treatment failure) is not known. Our objective was to determine if aspirin treatment failure predicts recurrent ischemic stroke and/or death. METHODS: We performed a post-hoc analysis of data from the National Institute of Neurological Disorders and Stroke (NINDS) intravenous recombinant tissue plasminogen activator (rt-PA) trial and the Trial of ORG 10172 in Acute Stroke Treatment (TOAST). Multivariate analysis was used to calculate the odds ratio (OR) of recurrent stroke and recurrent stroke or death for aspirin treatment failure patients for the duration of available follow-up (3 months for TOAST patients; 12 months for NINDS rt-PA trial patients). RESULTS: The rate of aspirin treatment failure was 40% and 35% among 1275 patients and 624 patients recruited in the TOAST and NINDS rt-PA trials, respectively. The risk of stroke and death at 3 months and 1 year was not higher among patients classified as aspirin treatment failures among the TOAST (OR 1.1; 95% confidence interval [CI] 0.8-1.6; P = .7) or NINDS rt-PA trial patients (OR 0.8; 95% CI 0.6-1.3; P = .4), respectively. In subgroup analysis, aspirin treatment failure was not found to be associated with recurrent stroke or with the combined endpoint of stroke and death among categories defined by etiologic subtype, including those with large artery atherosclerosis. CONCLUSIONS: In a post-hoc analysis of 2 randomized ischemic stroke trials, aspirin treatment failure was not found to be associated with an increased risk of recurrent stroke or death.