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It is currently unclear whether midlife systemic inflammation promotes the development of white matter (WM) abnormalities and small vessel disease in the elderly. We examined the association of midlife systemic inflammation with late-life WM hyperintensity volume, deep and periventricular WM microstructural integrity (fractional anisotropy and mean diffusivity [MD]), cerebral infarcts, and microbleeds in a biracial prospective cohort study.Linear and logistic regression examined the relation between midlife high-sensitivity C-reactive protein (CRP)—a nonspecific marker of inflammation—and brain magnetic resonance imaging markers assessed 21 years later in the Atherosclerosis Risk in Communities Study.We included 1485 participants (baseline age, 56; 28% black). After adjusting for demographic factors and cardiovascular disease, each SD increase in midlife CRP was associated with lower fractional anisotropy (−0.09 SD; 95% confidence interval, −0.15 to −0.02) and greater MD (0.08 SD; 95% confidence interval, 0.03–0.15) in deep WM and lower fractional anisotropy (−0.07 SD; 95% confidence interval, −0.13 to 0.00) in periventricular WM. We found stronger associations between CRP and periventricular WM microstructural integrity among black participants (P interaction=0.011). Although an association between higher CRP levels and greater WM hyperintensity volume was found only among APOE ε4-positive participants in our primary analysis (0.14 SD; 95% confidence interval, 0.01–0.26; P interaction=0.028), this relationship extended to the entire sample after accounting for differential attrition. Midlife CRP was not associated with the presence of cerebral infarcts or microbleeds in late life.Our findings support the hypothesis that midlife systemic inflammation may promote the development of chronic microangiopathic structural WM abnormalities in the elderly.