White matter hyperintensities (WMHs) associate with both cognitive slowing and motor dysfunction in the neurologically normal elderly. A full understanding of the pathology underlying this clinicoradiologic finding is currently lacking in autopsy-confirmed normal brains. To determine the histopathologic basis of WMH seen on magnetic resonance imaging, we studied the relationship between postmortem fluid-attenuated inversion recovery (FLAIR) intensity and neuropathologic markers of WM lesions (WMLs) that correspond to WMH in cognitively normal aging brains. Samples of periventricular (n = 24), subcortical (n = 26), and normal-appearing WM (NAWM, n = 31) from 4clinically and pathologically confirmed normal cases were examined. The FLAIR intensity, vacuolation, and myelin basic protein immunoreactivity loss were significantly higher in periventricular WML versus subcortical WML; both were higher than in NAWM. The subcortical WML and NAWM had significantly less axonal loss, astrocytic burden, microglial density, and oligodendrocyte loss than those of the periventricular WML. Thus, vacuolation, myelin density, and small vessel density contribute to the rarefaction of WM, whereas axonal density, oligodendrocyte density, astroglial burden, and microglial density did not. These data suggest that the age-related loss of myelin basic protein and the decrease in small vessel density may contribute to vacuolation of WM. Vacuolation enables interstitial fluid to accumulate, which contributes to the prolonged T2 relaxation and elevated FLAIR intensity in the WM.