Magnetic resonance imaging (MRI) is the main tool for detecting central nervous system lesions in MS. However, classical anatomical MRI is unable to assess exactly disease related injury in normal-appearing brain tissue and to give information about the functional consequences of the disease, explaining weak correlation frequently observed between lesion load and clinical data. Recently, functional brain imaging techniques have provided new insights concerning pathophysiological processes of the disease. Among them Positron Emission Tomography (PET), a sensitive technique to evaluate functional consequences of tissue injury in other neurological diseases, has rarely been used in MS. Seventeen Relapsing-Remitting (RR-) MS patients with low disability at the early stage of the disease underwent measurements of cerebral metabolic rate of glucose (rCMRglu) in resting state by PET using [(18)F] fluorodeoxyglucose (FDG) and assessment of regional cortical and white matter lesion volume (LV), using an in-house-developed semi-automatic method, was done at the same time on MRI. rCMRglu of MS patients was compared with rCMRglu of 18 normal control subjects using univariate SPM99 analysis through Matlab 5 and correlations between rCMRglu and LV were tested using multivariate linear regression using SPM99. Statistical threshold was set at p<0.05 corrected for multiple comparisons and correlations. Compared to controls, reduced rCMRglu was found in the right thalamus (p<0.001), in bilateral cerebellum (p<0.05 for right and p<0.01 for left) and the posterior part of left inferior parietal cortex (p<0.05). In addition, higher rCMRglu in patients compared to controls was observed in left inferior frontal cortex, left (anterior part) and right inferior parietal cortex (p<0.001). rCMRglu in right thalamus correlates negatively with different LV: total LV, total juxtacortical and/or overlapping cortico-subcortical LV, total and frontal deep white matter LV. rCMRglu of the right superior frontal cortex negatively correlated with total and parieto-occipital deep white matter LV. The results of this study, performed in a group of recent RR-MS patients with low disability, suggest that demyelinating lesions in MS mainly have a remote effect on cortical, basal ganglia and cerebellum metabolism and that regional cortical compensatory mechanisms may be observed concurrently.