OBJECTIVES: To evaluate the impact of various antihypertensive drugs on secondary stroke prevention in a real-life setting. DESIGN: Nationwide historic cohort study. SETTING: French healthcare system data (SNDS). PARTICIPANTS: Adults hospitalised for ischaemic stroke between 2014 and 2015 were followed up until December 2021 and stratified based on the presence of atrial fibrillation (AF). OUTCOME MEASURES: Risk of stroke recurrence was assessed using a time-dependent Cox cause-specific model accounting for changes in drug exposure. We also investigated the risk of major adverse cardiovascular events (MACE) or all-cause death. Models were adjusted on stroke characteristics, coprescriptions and co-morbidities, at inclusion and across follow-up. RESULTS: Among 54 764 patients without AF (median age 71; 46% women) and 17 960 with AF (median age 79; 51% women), stroke recurrence occurred in 11% and 13%, respectively. In non-AF patients, reduced recurrence risk was associated only with use of calcium channel blockers (adjusted HR (aHR) 0.91, 95% CI 0.86 to 0.97), thiazide diuretics (aHR 0.90, 95% CI 0. 83 to 0.97), loop diuretics (aHR 0.86, 95% CI 0.77 to 0.95) and potassium-sparing agents (aHR 0.83, 95% CI 0.70 to 0.98). In AF patients, only potassium-sparing agents (aHR 0.82, 95% CI 0.69 to 0.99) were associated with reduced recurrence risk. All antihypertensive drugs, apart from loop diuretics, were associated with a reduced risk of MACE or all-cause death. CONCLUSIONS: In this large cohort, only diuretics and calcium channel blockers were associated with a reduced risk of recurrent stroke. Most antihypertensive drugs, however, may be more effective in overall cardiovascular prevention.