Diffusion tensor imaging (DTI) is sensitive to white matter (WM) damage in multiple sclerosis (MS), not only in focal lesions but also in the normal-appearing WM (NAWM). However, DTI indices can also be affected by natural spatial variation in WM, as seen in crossing and dispersing white matter fibers. Neurite orientation dispersion and density imaging (NODDI) is an advanced diffusion-weighted imaging technique that provides distinct indices of fiber density and dispersion. We performed NODDI of lesion tissue and NAWM in five MS patients and five controls, comparing the technique with traditional DTI. Both DTI and NODDI identified tissue damage in NAWM and in lesions. NODDI was able to detect additional changes and it provided better contrast in MS-NAWM microstructure, because it distinguished orientation dispersion and fiber density better than DTI. We showed that NODDI is viable in MS patients and that it offers, compared with DTI parameters, improved sensitivity and possibly greater specificity to microstructure features such as neurite orientation.