BACKGROUND AND PURPOSE: MR imaging is essential for MS diagnosis and management, yet it has limitations in assessing axonal damage and remyelination. Gadolinium-based contrast agents add value by pinpointing acute inflammation and blood-brain barrier leakage, but with drawbacks in safety and cost. Neurite orientation dispersion and density imaging (NODDI) assesses microstructural features of neurites contributing to diffusion imaging signals. This approach may resolve the components of MS pathology, overcoming conventional MR imaging limitations. MATERIALS AND METHODS: Twenty-one subjects with MS underwent serial enhanced MRIs (12.6 6 9 months apart) including NODDI, whose key metrics are the neurite density and orientation dispersion index. Twenty-one age-and sex-matched healthy controls underwent unenhanced MR imaging with the same protocol. Fifty-eight gadolinium-enhancing and non-gadolinium-enhancing lesions were semiautomatically segmented at baseline and follow-up. Normal-appearing WM masks were generated by subtracting lesions and dirty-appearing WM from the whole WM. RESULTS: The orientation dispersion index was higher in gadolinium-enhancing compared with non-gadolinium-enhancing lesions; logistic regression indicated discrimination, with an area under the curve of 0.73. At follow-up, in the 58 previously enhancing lesions, we identified 2 subgroups based on the neurite density index change across time: Type 1 lesions showed increased neurite density values, whereas type 2 lesions showed decreased values. Type 1 lesions showed greater reduction in size with time compared with type 2 lesions. CONCLUSIONS: NODDI is a promising tool with the potential to detect acute MS inflammation. The observed heterogeneity among lesions may correspond to gradients in severity and clinical recovery after the acute phase. ABBREVIATIONS: AD ¼ axial diffusivity; DAWM ¼ dirty-appearing white matter; FA ¼ fractional anisotropy; FU ¼ follow-up; GEL ¼ gadolinium-enhancing lesion; HC ¼ healthy control; MD ¼ mean diffusivity; NAWM ¼ normal-appearing white matter; NDI ¼ neurite density index; NGEL ¼ non-gadolinium-enhancing lesion; NODDI ¼ neurite orientation dispersion and density Imaging; nODI ¼ normalized orientation dispersion index; ODI ¼ orientation dispersion index; RD ¼ radial diffusivity; VEC ¼ extra-neurite compartment C onventional MR imaging is essential for MS diagnosis and management, specifically for demonstrating WM lesion dissemination in space (involvement of .1 CNS region) and time (across time accumulation). 1 Conventional MR imaging, however, lacks specificity in characterizing MS WM lesions after the acute phase; all lesions show a similar radiologic appearance on T2WI, irrespective of the degree of inflammation, axonal loss, gliosis,