OBJECTIVE: To determine the relation of gray matter (GM) and white matter (WM) brain volumes, and WM lesion load, with clinical outcomes 20 years after first presentation with clinically isolated syndrome suggestive of multiple sclerosis (MS). METHODS: Seventy-three patients were studied a mean of 20 years from first presentation with a clinically isolated syndrome (33 of whom developed relapsing-remitting MS and 11 secondary-progressive MS, with the rest experiencing no further definite neurological events), together with 25 healthy control subjects. GM and WM volumetric measures were obtained from three-dimensional T1-weighted brain magnetic resonance images using Statistical Parametric Mapping 2. RESULTS: Significant GM (p < 0.001) and WM atrophy (p = 0.001) was seen in MS patients compared with control subjects. There was significantly more GM, but not WM atrophy, in secondary-progressive MS versus relapsing-remitting MS (p = 0.003), and relapsing-remitting MS versus clinically isolated syndrome (p < 0.001). GM, but not WM, fraction correlated with expanded disability status scale (r(s) = -0.48; p < 0.001) and MS Functional Composite scores (r(s) = 0.59; p < 0.001). WM lesion load correlated with GM (r(s) = -0.63; p < 0.001), but not with WM fraction. Regression modeling indicated that the GM fraction explained more of the variability in clinical measures than did WM lesion load. INTERPRETATION: In MS patients with a relatively long and homogeneous disease duration, GM atrophy is more marked than WM atrophy, and reflects disease subtype and disability to a greater extent than WM atrophy or lesions.