Background: Small-vessel disease (SVD) plays a crucial role in cardiac and brain ischemia, but little is known about potential interrelation between both. We retrospectively evaluated 370 patients, aiming at assessing the interrelation between cardiac and brain SVD by using quantitative Rb-82 cardiac PET/CT and brain MRI. Results: In our population of 370 patients, 176 had normal myocardial perfusion, 38 had pure cardiac SVD and 156 had obstructive coronary artery disease. All underwent both a cardiac Rb-82 PET/CT and a brain 1.5T or 3T MRI. Left-ventricle myocardial blood flow (LV-MBF) and flow reserve (LV-MFR) were recorded from Rb-82 PET/CT, while Fazekas score, white matter lesion (WMab) volume, deep gray matter lesion (GMab) volume, and brain morphometry (for z-score calculation) using the MorphoBox research application were derived from MRI. Groups were compared with Kruskal-Wallis test, and the potential interrelation between heart and brain SVD markers was assessed using Pearson's correlation coefficient. Patients with cardiac SVD had lower stress LV-MBF and MFR (P < 0.001) than patients with normal myocardial perfusion; Fazekas scores and WMab volumes were similar in those two groups (P > 0.45). In patients with cardiac SVD only, higher rest LV-MBF was associated with a lower left-putamen (rho = - 0.62, P = 0.033), right-thalamus (rho = 0.64, P = 0.026), and right-pallidum (rho = 0.60, P = 0.039) z-scores and with a higher GMab volume. Lower stress LV-MBF was associated with lower left-caudate z-score (rho = 0.69, P = 0.014), while lower LV-MFR was associated with lower left (rho = 0.75, P = 0.005)- and right (rho = 0.59, P = 0.045)-putamen z-scores, as well as higher right-thalamus GMab volume (rho = - 0.72, P = 0.009). Conclusion: Significant interrelations between cardiac and cerebral SVD markers were found, especially regarding deep gray matter alterations, which supports the hypothesis of SVD as a systemic disease.