Background: Polypharmacy is very common in older persons and it is associated with inappropriate prescribing and potential drug-drug interactions (DDIs). Aims of this study were to identify prevalence of DDIs in older persons with acute stroke and to evaluate the association between stroke and DDIs. Methods: One hundred forty-six patients admitted with diagnosis of acute stroke were enrolled. The therapeutic regimen of patients was analyzed at admission to identify the number of DDIs, prevalence and sorts of serious DDIs according to subtype of acute stroke (ischemic or hemorrhagic) and to its recurrence. Results: Five hundred eighty-two DDIs were identified: 18 mild, 415 moderate and 149 serious. Sixty-one percent of patients were exposed to at least one serious DDI. A higher percentage of patients were exposed to at least one serious DDI among those with a recurring ischemic event compared to those with a first event (74 vs. 50%; p < 0.01, respectively). Serious DDIs potentially associated with an increased risk of a cerebral event were identified in 19 (17%) patients with ischemic stroke, and in 7 (19%) patients with hemorrhagic stroke. Conclusions: The prevalence of serious DDIs was high in aging patients with acute stroke but different according to subtype and recurrence of the cerebrovascular event.