This study investigates the heterogeneity of multiple sclerosis (MS) by performing an exploratory factor analysis on neuropathological data from 226 MS donors in the Netherlands Brain Bank autopsy cohort. Three distinct dimensions were identified: Dimension 1 is characterized by a predominance of remyelinated and inactive lesions, higher proportions of active and mixed lesions, and foamy microglia morphology, and is positively correlated with more severe disease, B and T cell presence, and neuroaxonal damage. Dimension 2 is associated with active lesions, reactive sites, and nodules, and is linked to less severe disease, specific cortical lesion patterns, and MS risk variants in the human leukocyte antigen (HLA) region. Dimension 3 shows increased lesional pathology with more mixed and inactive lesions and ramified microglia morphology, and is associated with longer disease duration, subpial cortical lesions, less adaptive immune system involvement, and less axonal damage. These dimensions may represent demyelination and immune cell activity, microglia (re)activity, and loss of lesion activity and scar formation, respectively. The findings highlight the importance of understanding the interplay between these pathological characteristics to better understand MS heterogeneity and its association with genetic predictors and disease outcomes.This study investigates the heterogeneity of multiple sclerosis (MS) by performing an exploratory factor analysis on neuropathological data from 226 MS donors in the Netherlands Brain Bank autopsy cohort. Three distinct dimensions were identified: Dimension 1 is characterized by a predominance of remyelinated and inactive lesions, higher proportions of active and mixed lesions, and foamy microglia morphology, and is positively correlated with more severe disease, B and T cell presence, and neuroaxonal damage. Dimension 2 is associated with active lesions, reactive sites, and nodules, and is linked to less severe disease, specific cortical lesion patterns, and MS risk variants in the human leukocyte antigen (HLA) region. Dimension 3 shows increased lesional pathology with more mixed and inactive lesions and ramified microglia morphology, and is associated with longer disease duration, subpial cortical lesions, less adaptive immune system involvement, and less axonal damage. These dimensions may represent demyelination and immune cell activity, microglia (re)activity, and loss of lesion activity and scar formation, respectively. The findings highlight the importance of understanding the interplay between these pathological characteristics to better understand MS heterogeneity and its association with genetic predictors and disease outcomes.