Postmortem MRI-guided tissue sampling significantly enhances the yield of MS lesions in autopsy material, but so far it is unknown whether abnormalities concur with blood-brain barrier alterations. Here we sampled MS lesions with focal and diffuse abnormalities (diffusely abnormal white matter; DAWM) on MRI; both were coupled to the presence of MS lesions upon neuropathological examination. Extravascular distribution of fibrinogen, indicating BBB disturbance, was observed in so-called (p)reactive lesions that reflect discrete areas of microglial activation without demyelination within an otherwise normal appearing white matter. Leakage became more extensive in active demyelinating MS lesions to chronic inactive lesions. An enlargement of the perivascular (Virchow-Robin) space containing infiltrated leukocytes was associated with both DAWM and focal abnormalities on postmortem MRI. This study shows for the first time that in MS brain changes in the vasculature take place not only in focal lesions but also in DAWM as detected by postmortem MRI. © 2005 Elsevier Inc. All rights reserved.