Background: Cigarette smoking is a known risk factor for cardiovascular disease, including ischemic stroke. The literature regarding the rate of persistent smoking after acute ischemic stroke and its effect on subsequent cardiovascular events is scarce. With this study, we aimed to report the rate of persistent smoking after ischemic stroke and the association between smoking status and major cardiovascular outcomes. Methods: This is a post-hoc analysis of the SPS3 trial (Secondary Prevention of Small Subcortical Strokes). Patients were divided into 4 groups based on smoking status at trial enrollment: (1) never smokers, (2) former smokers, (3) smokers who quit at 3 months, and (4) persistent smokers. The primary outcome is a major adverse cardiovascular events composite of stroke (ischemic and hemorrhagic), myocardial infarction, and mortality. Outcomes were adjudicated after month 3 of enrollment until an outcome event or the end of study follow-up. Results: A total of 2874 patients were included in the study. Of the total cohort, 570 patients (20%) were smokers at enrollment, of whom 408 (71.5%) patients continued to smoke and 162 (28.4%) quit smoking by 3 months. The major adverse cardiovascular events outcome occurred in 18.4%, 12.4%, 16.2%, and 14.4%, respectively, in persistent smokers, smokers who quit, prior smokers, and never smokers. In a model adjusted for age, sex, race, ethnicity, education, employment status, history of hypertension, diabetes, hyperlipidemia, myocardial infarction, and intensive blood pressure randomization arm, the risk of major adverse cardiovascular events, and death were higher in the persistent smokers compared with never smokers (HR for major adverse cardiovascular events: 1.56 [95% CI, 1.16–2.09]; HR for death: 2.0 [95% CI, 2.18–3.12]). The risk of stroke, and MI did not differ according to smoking status Conclusions: Compared with never smoking, persistent smoking after acute ischemic stroke was associated with an increased risk of cardiovascular events and death. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00059306.