This study investigates the heterogeneity of multiple sclerosis (MS) by identifying three independent neuropathological dimensions using exploratory factor analysis (FAMD) on quantitative and qualitative neuropathology data from 226 MS donors in the Netherlands Brain Bank (NBB) autopsy cohort. The three dimensions represent distinct neuropathological patterns: (1) demyelination and immune cell activity associated with pathological and clinical progression, (2) microglia (re)activity and possibly lesion initiation, and (3) loss of lesion activity and scar formation. The dimensions were validated using clinical, neuropathological, and genetic data. Dimension 1 was associated with more severe disease, active lesions, and neuroaxonal damage. Dimension 2 was linked to less severe disease, specific cortical lesion patterns, and MS risk variants in the human leukocyte antigen (HLA) region. Dimension 3 was associated with longer disease duration, subpial cortical lesions, and less involvement of the adaptive immune system. The study highlights the importance of understanding the interplay between multiple pathological characteristics to understand MS heterogeneity and its association with genetic predictors and disease outcomes. The scores of donors on the dimensions can serve as an important starting point for further disentanglement of MS heterogeneity and translation into observations and interventions in living cohorts with MS. The findings suggest that the three dimensions may represent distinct pathogenetic mechanisms in MS. The study also shows that the dimensions are associated with clinical manifestations, comorbidities, and drug use. The results indicate that the three dimensions are independent of each other and reflect different aspects of MS pathology. The study provides a framework for understanding the heterogeneity of MS pathology and its association with genetic and clinical factors. The findings have implications for the development of targeted therapies for MS.This study investigates the heterogeneity of multiple sclerosis (MS) by identifying three independent neuropathological dimensions using exploratory factor analysis (FAMD) on quantitative and qualitative neuropathology data from 226 MS donors in the Netherlands Brain Bank (NBB) autopsy cohort. The three dimensions represent distinct neuropathological patterns: (1) demyelination and immune cell activity associated with pathological and clinical progression, (2) microglia (re)activity and possibly lesion initiation, and (3) loss of lesion activity and scar formation. The dimensions were validated using clinical, neuropathological, and genetic data. Dimension 1 was associated with more severe disease, active lesions, and neuroaxonal damage. Dimension 2 was linked to less severe disease, specific cortical lesion patterns, and MS risk variants in the human leukocyte antigen (HLA) region. Dimension 3 was associated with longer disease duration, subpial cortical lesions, and less involvement of the adaptive immune system. The study highlights the importance of understanding the interplay between multiple pathological characteristics to understand MS heterogeneity and its association with genetic predictors and disease outcomes. The scores of donors on the dimensions can serve as an important starting point for further disentanglement of MS heterogeneity and translation into observations and interventions in living cohorts with MS. The findings suggest that the three dimensions may represent distinct pathogenetic mechanisms in MS. The study also shows that the dimensions are associated with clinical manifestations, comorbidities, and drug use. The results indicate that the three dimensions are independent of each other and reflect different aspects of MS pathology. The study provides a framework for understanding the heterogeneity of MS pathology and its association with genetic and clinical factors. The findings have implications for the development of targeted therapies for MS.