Objectives Lacunar stroke had an unfavorable prognosis in the long term with a high risk of recurrent stroke, aspirin has been widely used to prevent ischemic stroke, but data on the effect of antiplatelet therapy on lacunar infarction are limited. We investigated the long-term effect of aspirin treatment on stroke recurrence risk in patients with lacunar stroke in a multicenter prospective cohort. Methods Between November 2000 and November 2001, 2000 consecutive stroke patients (age 35-74 years) were recruited from seven clinical centers. For the present study, a total of 544 patients with lacunar infarction were finally included in the analysis. The patients were divided into two groups (aspirin group, n = 342 and non-aspirin group, n = 202).The effect of aspirin on stroke recurrence was evaluated by using Kaplan-Meier analysis and Cox regression models. Results During a median 4.1-year follow-up for 544 patients with lacunar stroke, 99 recurrent strokes, 125 major vascular events (stroke, myocardial infarction, and vascular death), 31 vascular deaths, and 59 all-cause deaths were identified. Kaplan-Meier analysis showed that aspirin non-users had a higher risk of future recurrent stroke and of vascular events than did aspirin users (log-rank test, P = 0.049, 0.047, respectively). Aspirin significantly reduced the stroke recurrence in patients with lacunar stroke analyzed with multivariate stepwise analysis using model of Cox proportional hazards with backward elimination (HR = 0.67, 95% CI 0.45-0.99). Conclusion We concluded that aspirin significantly reduced stroke recurrence in patients with lacunar stroke.