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Introduction: Brain perivascular spaces (PVS) are associated with higher pulse pressures and may be imaging biomarkers of systemic arterial stiffness. We hypothesized that larger proximal arterial diameters act as effect modifiers between downstream PVS and surrogate measures of arterial stiffness.Methods: Stroke-free Northern Manhattan Study participants with brain MRI and carotid ultrasound were analyzed. Perivascular spaces were rated semi-quantitatively as ≤ 3 mm voids on axial T1 images without associated FLAIR hyperintensities. Intracranial brain arterial diameters were measured on MRA. The right common carotid artery (CCA) was assessed by high resolution B-mode ultrasound to obtain systolic and diastolic diameters. CCA stiffness was calculated as a ratio between logn transformed systolic-diastolic blood pressure and (systolic - diastolic diameter)/diastolic diameter. We created generalized linear models using and pulse pressure (PP) and CCA stiffness as predictors as independent variables and right anterior PVS score as the outcome, adjusting for demographics, risk factors, head size.Results: Among 941 participants (N=941, mean age 71 ± 9 year, 60% women, 66% Hispanic), PP was associated with PVS score (B=0.003, P=0.04) in an adjusted model. There was a statistical interaction between PP, right CCA diastolic diameter, and right intracranial arterial diameters as predictors of right anterior PVS score (P=0.03), but this interaction was not significant for posterior fossa PVS score (B=0.015, P=0.191), or when substituting right intracranial arterial diameters with the basilar artery diameter (B=-0.004, P=0.191). The association between PP (P=0.003) or carotid stiffness (P=0.002) with right anterior PVS score was greater among participants with larger right intracranial arterial and larger CCA diameters.Conclusions: Arterial stiffness is related to downstream PVS in those with larger proximal arterial diameters. These results suggest a mechanical effect of pulsatility on brain parenchyma and further studies are needed to enhance our understanding of the link between systemic hemodynamics and brain diseases such as dementia and stroke.