BACKGROUND AND PURPOSE: The role of juxtacortical lesions in brain volume loss in multiple sclerosis has not been fully clarified. The aim of this study was to explore the role of juxtacortical lesions on cortical atrophy and to investigate whether the presence of juxtacortical lesions is related to local cortical thinning in the early stages of MS. MATERIALS AND METHODS: A total of 131 patients with clinically isolated syndrome or with relapsing-remitting MS were scanned on a 3T system. Patients with clinically isolated syndrome were classified into 3 groups based on the presence and topography of brain lesions: no lesions (n < 24), only non-juxtacortical lesions (n < 33), and juxtacortical lesions and non-juxtacortical lesions (n < 34). Patients with relapsing-remitting MS were classified into 2 groups: only non-juxtacortical lesions (n < 10) and with non-juxtacortical lesions and juxtacortical lesions (n < 30). A juxtacortical lesion probability map was generated, and cortical thickness was measured by using FreeSurfer. RESULTS: Juxtacortical lesion volume in relapsing-remitting MS was double that of patients with clinically isolated syndrome. The insula showed the highest density of juxtacortical lesions, followed by the temporal, parietal, frontal, and occipital lobes. Patients with relapsingremitting MS with juxtacortical lesions showed significantly thinner cortices overall and in the parietal and temporal lobes compared with those with clinically isolated syndrome with normal brain MR imaging. The volume of subcortical structures (thalamus, pallidum, putamen, and accumbens) was significantly decreased in relapsing-remitting MS with juxtacortical lesions compared with clinically isolated syndrome with normal brain MR imaging. The spatial distribution of juxtacortical lesions was not found to overlap with areas of cortical thinning. CONCLUSIONS: Cortical thinning and subcortical gray matter volume loss in patients with a clinically isolated syndrome or relapsingremitting MS was related to the presence of juxtacortical lesions, though the cortical areas with the most marked thinning did not correspond to those with the largest number of juxtacortical lesions.