BACKGROUND AND PURPOSE Our aim was to evaluate the hypothesis that water diffusion alterations are present in normal-appearing white matter of patients with relapsing-remitting multiple sclerosis (RRMS) and to assess their change with time. MATERIALS AND METHODS Fifty-four subjects with clinically diagnosed RRMS, with disease duration of less than 12 months and an expanded disability status scale (EDSS) score of <3.5, underwent a diffusion 3T MR imaging study. The apparent diffusion coefficient (ADC) maps generated were compared with those of 18 control subjects. Eighteen of the 54 patients underwent MR imaging assessment at 3 and 6 months after baseline evaluation. Remitting patients were clinically and MR imaging stable for the 2 months before the study. All patients were drug-free for the 3 months before the study, and in the relapsing patients, the MR imaging was always performed before beginning treatment. RESULTS Mean ADC values showed significant differences when relapsing, remitting, and control patients were compared. The relapsing or remitting phase showed significant difference when compared both with controls (P < .01) and between them (P < .05). Comparing mean ADC values of patients with clinical disability (EDSS <2 versus EDSS >/=2) also provided significant differences with the control group (P < .01). The data of patients showing a relapsing episode during the longitudinal part of the study showed a significant difference compared with data from their remitting phase (P < .01). CONCLUSION Brain microstructural changes can be detected and correlate with clinical impairment during the stages of MS. These changes modify with time in the relapsing group.