Small vessel disease (SVD) is associated with stroke and dementia, however pathophysiological mechanisms are poorly understood, and effective treatments are lacking. Here, we determine the association between systemic arterial pulsatility and tissue-level cerebral pulsatility in patients with SVD, and its modulation by anti-hypertensive medication, using a novel analysis technique. We observe a significant association between systemic pulsatility and regional cerebral pulsatility, at baseline and on antihypertensive medication. The association was strongest in periventricular white matter most commonly affected by SVD. This regional dependence suggests that pulsatility is a pathophysiological factor underlying tissue damage in SVD, providing a potential treatment target.