We aimed to provide real-world evidence on the benefit of persistence with antiplatelet therapy (APT) on long-term all-cause mortality (ACM) in ischemic stroke patients aged 75 years and older. Newly diagnosed ischemic stroke patients aged 75 years and older who initiated aspirin or clopidogrel for the first time were chosen from 2003 to 2010 National Health Insurance Service-National Sample Cohort (NHIS-NSC) of Korea (n = 887), a random cohort sample accounting for 2.2% (n = 1,017,468) of total population (n = 46,605,433). Then subjects were divided into persistent (n = 556) and non-persistent (n = 321) groups according to the persistent status at 6 months. Survivor analysis was performed between the two groups and predictors of non-persistence were analyzed by multivariate logistic regression analysis. Patients were followed up until death or December 31, 2013. Non-persistence with APT was significantly associated with increased risk of ACM (adjusted hazard ration aHR 2.13, 95% confidence interval CI 1.72-2.65), cerebro-cardiovascular disease (CVD) mortality (aHR 2.26, 95% CI 1.57-3.24), and non-CVD mortality (aHR 2.06, 95% CI 1.5702.70). More comorbidities (Charlson comorbidity index score ≥ 6) (adjusted odds ratio aOR, 2.56, 95% CI 1.43-4.55), older age (aOR 1.52, 95% CI 1.11-2.09 for 80-84 years, aOR 1.73, 95% CI 1.17-2.57 for ≥85 years), and less than 4 total prescribed drugs (aOR 1.54, 95% CI 1.08-2.21) were independent predictors of non-persistence. Persistent with APT after ischemic stroke featured long-term mortality benefit even in patients aged 75 years and older. Thus, improving APT persistence for ischemic stroke patients in this age group is also recommended by understanding factors associated with non-persistence.