ABSTRACTBackground and PurposeAxonal injury is a key player of disability in persons with multiple sclerosis (pwMS). Yet, detecting and measuring it in vivo is challenging. The neurite orientation dispersion and density imaging (NODDI) proposes a novel framework for probing axonal integrity in vivo. NODDI at 3.0 Tesla was used to quantify tissue damage in pwMS and its relationship with disease progression.MethodsEighteen pwMS (4 clinically isolated syndrome, 11 relapsing remitting, and 3 secondary progressive MS) and nine age‐ and sex‐matched healthy controls underwent a brain MRI, inclusive of clinical sequences and a multi‐shell diffusion acquisition. Parametric maps of axial diffusivity (AD), neurite density index (ndi), apparent isotropic volume fraction (ivf), and orientation dispersion index (odi) were fitted. Anatomically matched regions of interest were used to quantify AD and NODDI‐derived metrics and to assess the relations between these measures and those of disease progression.ResultsAD, ndi, ivf, and odi significantly differed between chronic black holes (cBHs) and T2‐lesions, and between the latter and normal appearing white matter (NAWM). All metrics except ivf significantly differed between NAWM located next to a cBH and that situated contra‐laterally. Only NAWM odi was significantly associated with T2‐lesion volume, the timed 25‐foot walk test and disease duration.ConclusionsNODDI is sensitive to tissue injury but its relationship with clinical progression remains limited.