Important questions remain unanswered about the sequence of events leading to progressive and ultimately irreversible tissue damage in MS. This study was designed to investigate the pathological characteristics of, and function of, the blood-brain barrier within longstanding MS lesions using quantitative and Gd-DTPA enhanced MRI techniques. The ultrastructural appearances of postmortem lesions from a single, separate case of MS have been correlated with the MRI findings. Both MRI and ultrastructural analysis revealed considerable heterogeneity in the chronic lesions: some are 'closed' with no detectable extracellular water, but most are 'open' and show expansion of the extracellular space to as much as 87% of tissue area. This variable expansion probably results from differing degrees of axonal loss. Evidence of blood-brain barrier damage was found in only 17% of lesions, was less severe than that seen in acute lesions, and may result from repeated previous inflammatory insults. The findings imply progressive axonal loss in lesions as they age. It is possible that this loss is related to clinical progression of the disease.