We performed spin echo magnetic resonance imaging with and without application of an off-resonance saturation pulse in 43 patients with multiple sclerosis (MS), 10 age-matched controls, and 4 elderly asymptomatic patients with the radiological diagnosis of small-vessel disease. Magnetization transfer (MT) ratio images were obtained from these. All MS subgroups (primary progressive, secondary progressive, benign, early relapsing-remitting) showed significantly lower average lesion MT ratios than small-vessel disease patients. Secondary progressive MS patients showed significantly lower lesion MT ratios than those with benign disease, and there was an inverse correlation of disability with average lesion MT ratio. The degree of reduction of MT ratios is an indicator of the extent of tissue destruction. Thus, reduced MT ratios in MS may provide an indication of the degree of demyelination and axonal loss, both of which are likely to cause functional deficits in MS. We conclude that MT measurement is (1) a robust quantitative method that may increase the pathological specificity of magnetic resonance imaging, (2) has the potential to differentiate demyelination in MS from less destructive pathological changes, and (3) may be useful in monitoring modifications in tissue structure brought about by treatment.