The brain water fraction (R), the brain water transverse relaxation time (T2), the atrophy index (alpha) and the absolute concentration of the principal brain metabolites (NAA, Cho and Cr) were measured by localized proton magnetic resonance spectroscopy in the occipito-parietal cortex (mainly gray matter) of 15 relapsing-remitting (R-R) multiple sclerosis (MS) patients, 15 secondary progressive (SP) MS patients and 8 healthy subjects. Significantly lower values of N-acetylaspartate (NAA), creatine (Cr) and the NAA/Cr ratio in the occipito-parietal cortex were detected in SP MS patients than in R-R MS and control subjects (p < 0.01). Moreover, MS patients showed shorter T2 water relaxation times and reduced brain water fraction compared with controls. Higher atrophy indices were also detected in the mainly occipito-parietal gray matter of MS patients, particularly in those with the progressive form. These findings suggest that the pathological process in MS is not limited to either white matter lesions or normal-appearing white matter but extends into the cortical gray matter (occipito-parietal), particularly in the progressive form of the disease. This can involve changes in neural metabolism or neural shrinkage and neuron loss. The significant increase in atrophy indices could be the expression of the relatively higher cerebrospinal fluid signal from the occipito-parietal cortex, even in the absence of obvious cortical atrophy.