Background <p>Although recurrent ischemic stroke (IS) is associated with higher rates of mortality and comorbidities as well as an increased economic burden than the first attack, the choice of first-line antihypertensive agent for secondary prevention remains controversial.&#xa0;This study examined the efficacy of various antihypertensive agents for the secondary prevention of recurrent ischemic stroke in a real-world context.</p> Methods <p>Using the National Health Insurance Research Database, patients with first acute IS from 1 January 2000 to 31 December 2020 were enrolled. Using propensity score-based probability of treatment weighting, all participants were divided into other antihypertensive drugs (OHTND), angiotensin-converting-enzyme-inhibitors/angiotensin II-receptor-blockers (ACEI/ARB), and calcium-channel-blockers (CCB) cohorts. Primary outcome was difference in risk of recurrent IS, and secondary outcomes were all-cause mortality, stroke-related death, and major adverse cardiac and cerebrovascular events (MACCEs). Cox proportional hazards models were used to estimate the adjusted hazard ratio and 95% confidence intervals.</p> Results <p>Compared with the OHTND cohort, individuals in the ACEI/ARB and CCB cohorts had a 14% (<i>p</i> &lt; 0.001) and 15% (<i>p</i> &lt; 0.001) lower risk of recurrent IS, respectively. Individuals in the CCB cohort had a 37% (<i>p =</i> 0.006) higher risk of acute myocardial infarction compared with the OHTND cohort. Compared with ACEI users, ARB users experienced a 22% lower risk of recurrent IS, while ARB users had a 46% lower risk of stroke-related death.</p> Conclusions <p>The use of ACEI/ARB following acute IS was associated with a lower risk of recurrent IS. Our results not only corresponded to pre-existing randomized controlled trials (RCTs) but also addressed the knowledge gap regarding the choice of first-line antihypertensive agents following acute IS.</p>