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Low blood pressure (BP) has been related to increased risk of brain atrophy. As brain hypoperfusion might be a marker for impaired cerebral autoregulation, the risk of brain atrophy may be especially increased if BP is low in combination with brain hypoperfusion. We examined whether low BP was associated with brain atrophy and whether this association was stronger in patients with lower parenchymal cerebral blood flow (CBF), as an indicator of brain perfusion.Within the Second Manifestations of ARTerial disease-Magnetic Resonance study, a cohort study among 1309 patients with atherosclerotic disease, cross-sectional analyses were performed in 965 patients (mean age 58 ± 10 years) with available BP and CBF measures. Parenchymal CBF was measured with magnetic resonance angiography and was expressed per 100 ml brain volume. Brain segmentation was used to quantify cortical gray matter volume and ventricular volume (% of intracranial volume).Linear regression analyses, adjusted for age, sex, and vascular risk factors showed that the association of systolic BP and pulse pressure, but not diastolic BP, with cortical gray matter volume was modified by parenchymal CBF (P interaction <0.05). In patients with lower parenchymal CBF, but not in those with high parenchymal CBF, lower systolic BP and pulse pressure (per SD decrease) were associated with reduced cortical gray matter volume: β (95% confidence interval) −0.29% (−0.63; 0.00) and −0.34% (−0.69; −0.01).Our findings suggest that lower BP by itself is not sufficient to induce brain atrophy; however, lower SBP and lower pulse pressure in combination with lower parenchymal CBF increased the risk for cortical atrophy.