OBJECTIVE: The objectives of the present study were to assess brain atrophy in multiple sclerosis (MS) patients during different disease stages and to investigate by PET and [11C]PK11195, a marker of microglial activation, the relationship between inflammation, atrophy and clinically relevant measures. METHODS: Eight healthy subjects and 22 MS patients were included. Semiquantitative [11C]PK11195 uptake values, with normalization on cortical grey matter, were measured for magnetic resonance imaging T2- and T1-lesions and normal appearing white matter (NAWM). As atrophy index we used the ratio of the amount of white and grey matter divided by the ventricular size, using an optimized a priori based segmentation algorithm (SPM99). RESULTS: Atrophy was significantly greater in MS patients compared to age-matched controls. A significant correlation was found between brain atrophy and both disease duration and disability, as measured with the Expanded Disability Status Scale. For NAWM, [11C]PK11195 uptake increased with the amount of atrophy, while T2-lesional [11C]PK11195 uptake values decreased according to increasing brain atrophy. CONCLUSIONS: The present study suggests that brain atrophy, correlating with disease duration and disability, is directly related to NAWM and T2-lesional inflammation as measured by microglial activation.