ABSTRACT Objectives Delirium is a common and serious post-stroke complication. Early reperfusion by ameliorating brain damage could potentially prevent delirium after ischemic stroke, but the impact of this therapy on delirium remains unclear. We aimed to explore the association between reperfusion therapy (RT) and post-stroke delirium. Methods We retrospectively analyzed data from the PRospective Observational POLIsh Study on post-stroke delirium. Symptoms of delirium were examined during the first 7 days after admission and a diagnosis of delirium was made using Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria. We used logistic regression to examine the association between RT and delirium. Results We included 301 acute stroke patients (median age: 77; median NIHSS: 14; 55.1% female). In the whole group of patients, RT was associated with a lower odds of delirium (34.2% vs 44.8%; adjusted OR: 0.56, 95% CI: 0.32–0.96, p = 0.035). There was a significant interaction between RT and pre-stroke cognitive status. As a result, RT was associated with a lower odds of delirium in patients without premorbid cognitive decline (28.8% vs 48.2%; adjusted OR: 0.34, 95% CI: 0.17–0.66, p = 0.002) and a higher odds of delirium in patients with pre-stroke cognitive decline (72.7% vs 41.0%; adjusted OR: 3.55, 95% CI: 1.03–12.20, p = 0.040). Discussion The association between RT and delirium is modified by pre-stroke cognitive status. In patients without cognitive decline, RT is associated with a lower likelihood of delirium. Delirium should be considered as a relevant outcome in future controlled trials.