OBJECTIVE: Adiposity predictors, body mass index (BMI), waist circumference (WC), and blood leptin and total adiponectin levels were associated with components of cerebral small vessel disease (CSVD) and brain volumetry in 503 adults with CSVD who were ≥50 years of age and enrolled in the Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Imaging Cohort (RUN DMC). METHODS: RUN DMC participants were followed up for 9 years (2006-2015). BMI, WC, brain imaging, and dementia diagnoses were evaluated at baseline and follow-up. Adipokines were measured at baseline. Brain imaging outcomes included CSVD components, white matter hyperintensities, lacunes, microbleeds, gray and white matter, hippocampal, total brain, and intracranial volumes. RESULTS: Cross-sectionally among men at baseline, higher BMI, WC, and leptin were associated with lower gray matter and total brain volumes, and higher BMI and WC were associated with lower hippocampal volume. At follow-up 9 years later, higher BMI was cross-sectionally associated with lower gray matter volume, and an obese WC (>102 cm) was protective for ≥1 lacune or ≥1 microbleed in men. In women, increasing BMI and overweight or obesity (BMI ≥25 kg/m2 or WC >88 cm) were associated with ≥1 lacune. Longitudinally, over 9 years, a baseline obese WC was associated with decreasing hippocampal volume, particularly in men, and increasing white matter hyperintensity volume in women and men. CONCLUSIONS: Anthropometric and metabolic adiposity predictors were differentially associated with CSVD components and brain volumetry outcomes by sex. Higher adiposity is associated with a vascular-neurodegenerative spectrum among adults at risk for vascular forms of cognitive impairment and dementias.