The safety, tolerability, and efficacy data for antipsychotic drugs used in the acute phase of stroke are limited. The primary aim of this study was to examine the effectiveness and safety of typical and atypical antipsychotics on acute ischemic stroke mortality.This observational study was conducted in a retrospective cohort of patients selected from the 2010-2011 National Health Research Institute database in Taiwan. Patients were tracked for 1 month from the time of their first hospitalization for acute ischemic stroke. A nested case-control analysis was used to estimate the odds ratio (OR) of 30-day mortality associated with antipsychotic drug, adjusted for age, gender, disease severity, and comorbidities.The study cohort included 47,225 subjects with ischemic stroke, including 9445 mortality cases and 37,780 matched controls. After adjustment for the covariates, antipsychotics users before ischemic stroke are associated with a 73% decrease in the rate of mortality (OR 0.27; 95% CI 0.23-0.31). After ischemic stroke, the use of antipsychotics is associated with 87% decrease in the rate of mortality (OR 0.13; 95% CI 0.1-0.16). The users of conventional antipsychotics are associated with a 78% decrease in the rate of mortality (OR 0.22; 95% CI 0.18-0.26). The users of atypical antipsychotics are also associated with a 86% decrease in the rate of mortality (OR 0.14; 95% CI 0.12-0.17).We found that 1-month mortality among acute stroke patients treated with antipsychotics is significantly lower. The benefit on lower mortality was found not only among ischemic stroke patients who had received antipsychotics previously but also among patients who start antipsychotics after their stroke.