Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. Objectives: To assess the contributions of cortico-juxtacortical and corpus callosum lesions to multiple sclerosis diagnosis and to compare the value of ≥1 vs ≥3 periventricular lesions in clinically isolated syndromes (CIS). Methods: Step 1: We evaluated lesion topography classifications in 657 patients with CIS with stepwise Cox proportional hazards regression models considering second attack as the outcome. Step 2: We established 2 dissemination in space (DIS) versions according to the periventricular lesion cutoffs of ≥1 and ≥3 and assessed their performance at 10 years with second attack as the outcome, first individually and then combined with dissemination in time (DIT) in all cases (n 5 326), by age, and by CIS topography. Results: Step 1: The models (hazard ratios [95% confidence interval]) favored ≥1 over ≥3 periventricular lesions (2.5 [1.7-3.6]) and cortico-juxtacortical over juxtacortical lesions (1.4 [1.0-1.8]). Callosal lesions were not selected. Step 2: DIS specificity with ≥1 periventricular lesions was slightly lower than with ≥3 (59.1 vs 61.4) and the same after adding DIT (88.6). Regarding age, ≥3 periventricular lesions improved DIS specificity over ≥ 1 lesions in the 40-49 years of age bracket (66.7 vs 58.3). This difference disappeared when adding DIT (83.3). Optic neuritis had a similar pattern when evaluating CIS topographies. Conclusions: Our results comply with the Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) consensus recommendation of combining cortical and juxtacortical lesions into a single term when possible. Concerning periventricular lesions, maintaining the current $1 cutoff in the McDonald criteria does not compromise specificity in typical CIS cases, but attention should be paid to older patients or optic neuritis cases.