Background: The issue of whether prior antiplatelet use favorably affects stroke severity is currently unresolved. In this study, we evaluated the effect of antiplatelet use on clinical stroke severity and ischemic lesion volume, and assessed the confounding effect of laboratory-defined aspirin resistance on this relationship. Methods: Admission National Institutes of Health Stroke Scale (NIHSS) score, ischemic lesion volumes on diffusion-weighted imaging (DWI), and in vitro aspirin resistance, in addition to other pertinent stroke features, were determined in a series of ischemic stroke patients. Univariate and multivariate analyses were performed to compare clinical and imaging markers of stroke severity among patients with and without prior antiplatelet use, taking into consideration the presence or absence of aspirin resistance. Results: Antiplatelet users experienced more severe strokes, per NIHSS score, in comparison to antiplatelet-naive patients (P = .007). No significant difference was observed with respect to admission DWI lesion volume. When analyses were repeated after adjustment for stroke subtype and other confounders, no association was observed between antiplatelet use and stroke severity. On the other hand, NIHSS scores were significantly higher in aspirin-unresponsive patients than in both aspirin responders (P = .049) and aspirin nonusers (P = .005). Conclusion: We were unable to demonstrate a substantial positive influence of prestroke antiplatelet usage on stroke severity. Although the presence of more severe strokes among patients with laboratory resistance suggests a protective influence of aspirin sensitivity on stroke severity, the hypothesis could not be validated as no difference was observed among aspirin-naive and aspirin-sensitive patients with respect to admission NIHSS score or DWI lesion volume.