ObjectivesThe effect of pre-stroke use of aspirin on small subcortical infarct dimensions or outcomes is not well described. We aimed to bridge this knowledge gap amongst a well-described and heterogeneous patient population. Materials and MethodsWe performed a post-hoc analysis of the Secondary Prevention of Small Subcortical Stroke (SPS3) trial. The primary exposure was aspirin use ≤7 days of index stroke. The primary outcomes were infarct dimensions. Functional outcomes by modified Rankin Scale (mRS) was a secondary outcome. Age restricted (≥55 years) subgroup analyses were performed as a sensitivity analysis. Descriptive statistical and regression modeling were performed for data analysis. ResultsWe included 1423 participants of which 453(31.8 %) used aspirin. Aspirin use was associated with more cardiovascular risk diagnoses. Maximal infarct diameter did not differ with pre-stroke aspirin use (11.3±4.2 mm versus 11.8±4.1 mm, p=0.057) however infarct area was smaller with exposure (126.4±90.0 mm2 versus 137.4±97.0 mm2, p=0.037) regardless of aspirin strength. Participants ≥55 years had smaller infarct diameters (11.1±4.2 mm versus 11.9±4.4 mm, p=0.019) and area (123.4±87.1 mm2 versus 130.6±93.2 mm2, p=0.037) with aspirin use. mRS did not significantly differ in our analyses. ConclusionsIn this post-hoc analysis of the SPS3 trial, pre-stroke aspirin use was associated with a smaller infarct area regardless of aspirin strength and without impact on functional outcomes. These findings were more pronounced in participants ≥55 years. Registrationhttps://clinicaltrials.gov/study/NCT00059306?term= %22sps3 %22&rank=1