We combined diffusion tensor imaging (DTI) measures of the corpus callosum (CC) and the superior longitudinal fascicle (SLF) with calculation of brain atrophy in 53 patients with relapsing-remitting multiple sclerosis (MS) and 15 healthy controls, to analyze their interrelation and their correlation with disease duration and clinical impairment. The lateral ventricle volume in MS patients was increased; the fractional anisotropy in the CC was decreased as was the fiber volume. Perpendicular (in the literature also referred to as radial) diffusivity (ped), which reflects the diffusion perpendicular to the long axis of the axons within the fiber bundle, was increased in the SLF and the posterior CC, but contrary to our predictions, parallel (also called axial) diffusivity (pad) that refers to the amount of diffusion in the direction of the axon was increased, too. Brain atrophy and DTI-derived parameters were highly intercorrelated and both correlated with disease duration. Discriminant analysis showed that DTI-derived atrophy measures are superior to brain atrophy measures in classifying patients and controls. In light of our results, animal studies focusing on demyelination and axonal loss are reinterpreted. Copyright © 2009 by the American Society of Neuroimaging.