We performed a clinical and magnetic resonance (MR) longitudinal study in 19 patients with benign multiple sclerosis (MS) to achieve a better definition of the nature of disability in MS. Patients with higher lesion volumes on conventional T2-weighted images at entry were those with more frequent relapses (p = 0.0004) and more new MR lesions (p = 0.003) during the follow up. However, 1/3 of these new lesions were located periventricularly and about 2/3 were small or intermediate in size. Two of the 11 patients (18%) with higher lesion volumes at entry developed progressive neurological deficits: in these two patients the new lesions seen on conventional T2 images had lower magnetization transfer ratios (p = 0.005) than those present in patients who remained clinically stable and a marked increase in hypointense lesion volumes on T1-weighted images was also found. Spinal cord cross-sectional area at C5 and MTR values for the seemingly normal white matter were similar to those found in normal controls. This study suggests that patients with benign MS have two different patterns of disease evolution, one characterized by very low clinical and MR activities, the other in which the lack of disabling symptomatology might be related to factors like site, size and nature of lesions. It also indicates that in patients with benign MS and high MR lesion loads the risk of developing a secondary progressive form of the disease is still present even after many years after onset.