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Background: Cerebral small vessel disease is related to widespread endothelial dysfunction, and suspected hypoperfusion at the level of the microcirculation. Lacunar infarcts are a major manifestation of small vessel disease, and result in significant long-term neurological morbidity and mortality. Congenital hypoplastic variants of the vessels of the Circle of Willis may result in impairment of collateral channels at the time of ischemia.Hypothesis: We hypothesized that lateralization of first-ever lacunar infarcts is related to relative hypoperfusion of the ipsilateral hemisphere due to asymmetric hypoplasia of the vessels of the Circle of Willis and inadequate side-to-side collateral circulation.Methods: We analyzed 40 consecutive patients that presented to a stroke center with a first-ever supratentorial lacunar infarct. All patients were able to undergo intracranial vascular imaging. Patients with significant large-vessel disease (even if asymptomatic) were excluded. A neuroradiologist, blinded to the laterality of the lacunar infarct, assessed for lateralized hypoplasia of the Circle of Willis (either anteriorly at the level of the A1 artery and AComA as one functional unit, or posteriorly at the level of the PCA and PComA as one functional unit). Proportions of ipsilateral and contralateral hypoplasia were compared directly, as well as with historical controls, with the chi-squared test.Results: Among analyzed patients, ipsilateral and contralateral anterior pathway hypoplastic variants were not significantly different from historical controls (p=0.145 and p=0.99 respectively). However, ipsilateral and contralateral posterior pathway hypoplastic variants were significantly different from historical controls (p<0.001 for both). There was no statistical difference between ipsilateral and contralateral posterior pathway hypoplasia (p=0.21).Conclusion: Hypoplasia of the posterior part of the Circle of Willis is significantly more common among patients with first-ever lacunar stroke, compared to historical controls. However, the asymmetry of hypoplasia does not affect the laterality of first-ever lacunar infarct. Further studies are required to explain this phenomenon.