Background: A significant proportion of ischemic strokes occur while using aspirin and therefore can be considered as clinical aspirin resistance. Apart from this clinical description, aspirin resistance can be defined by laboratory tests of in vitro platelet reactivity. The correlation between clinical and laboratory-defined resistance, however, is far from perfect, and the heterogenous nature of stroke pathophysiology might play a role in this discrepancy. Methods: The level of in vitro platelet inhibition by aspirin was prospectively evaluated using the VerifyNow Aspirin Assay (Accumetrics, San Diego, CA) in patients presenting with ischemic stroke while using aspirin (n = 78). Demographic and clinical features, including stroke etiology, were compared among patients with and without sufficient level of platelet inhibition and an additional set of patients suffering from stroke while not using aspirin (n = 257). Similar analyses were performed in a separate validation cohort. Results: Laboratory evidence of insufficient platelet inhibition was detected in 16 of 78 patients (21%) with clinical aspirin resistance. On the other hand, 30 patients (38%) had stroke etiologies well known to be inadequately responsive to aspirin therapy. Overall, laboratory-defined resistance by itself could be considered to be accountable for the ischemic event in only 15% of these patients. The corresponding figure was 9% in validation cohort. Patients with sufficient level of platelet inhibition were more likely to harbor an anticoagulant responsive etiology compared with aspirin naive patients (odds ratio, 2.0; P = .033). Conclusions: Our findings highlight that laboratory aspirin resistance because of insufficient platelet inhibition is relatively uncommon, whereas pathophysiologic resistance, signifying the presence of etiologies that cannot be efficiently treated with aspirin treatment, is a major contributor of clinical resistance in ischemic stroke.