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Background: Cerebral microbleeds (CMBs) have been associated with cognitive dysfunction. However, characterization of CMBs and cognitive dysfunction in a large population of stroke patients is lacking. We aimed to characterize the association of CMBs with cognitive function in lacunar stroke patients and the response to assigned treatments in the Secondary Prevention of Small Subcortical Strokes (SPS3) trial.Methods: SPS3 was a randomized trial comparing two systolic blood pressure targets and two antiplatelet regimens in 3020 dementia-free patients with symptomatic, MRI-confirmed lacunar stroke. Participants underwent detailed neuropsychological testing covering multiple domains, including short delay recall, long delay recall, discriminability, block design, symbol search, grooved pegboard, controlled oral word association and clock drawing, at baseline and then annually for 5 years. Participants with axial MRI T2*- GRE sequences allowing for CMB detection and Cognitive Abilities Screening Instrument (CASI) Z scores available at baseline were included in the current analysis.Results: CMBs were present in 30% of 1225 eligible patients (mean age 63 years, 35% women) with median follow up of 3 years. Patients with CMBs had greater proportion of mild cognitive impairment (MCI; 56% vs. 42%, p<0.0001) and lower cognitive scores at baseline (mean CASI Z score -0.9 vs. -0.5, p<0.0001), including significantly lower scores across most of the individual cognitive domains tested. During follow-up, in 578 participants without MCI, there was no difference in the rate of incident MCI in patients with CMBs (29%, 41/143) and those without CMBs (26%, 111/435; p=0.50). Trends in cognitive decline over time were not statistically significantly different between the two groups. There were no interactions between CMBs and treatment assignments for cognitive outcomes.Conclusions: In this largest reported cohort assessing the association between CMBs and post-stroke cognitive impairment, CMBs were associated with lower cognitive scores and greater rates of MCI at baseline. However, changes over time in cognition were similar in lacunar stroke patients with and without CMBs who receive adequate vascular risk management.