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Multiple sclerosis (MS) is a heterogeneous disorder with regards to clinical presentation and pathophysiology. Stratification into biologically distinct subgroups could enhance prognostication and efficacious allocation to disease-modifying therapies. In this study, we identified MS subgroups by performing a clustering analysis on neuropathology data collected for MS donors in the Netherlands Brain Bank (NBB) autopsy cohort. The input dataset contained detailed information on white matter lesion load, the proportion of active, mixed active/inactive, inactive and remyelinating lesions, microglia morphology in these lesions, and the presence of microglial nodules, perivascular cuffs and cortical lesions for 228 donors. A factor analysis was performed to reduce noise and redundancy prior to hierarchical clustering with K-means consolidation. Four subgroups with distinct patterns of white matter lesions were identified. These were subsequently validated with additional clinical, neuropathological and genetic data. The subgroups differed with regards to disease progression and duration, the timing of motor, sensory and other relevant signs and symptoms, patterns of cortical lesions and the presence of B cells. Age at MS onset and sex, previously associated with milder forms of MS, did not differ between the subgroups; the subgroups could also not be distinguished based on the manifestation of clinical signs and symptoms. The available genetic data was used to calculate MS polygenic risk scores (PRSs) for donors included in the NBB cohort. The MS PRS did not differ between the subgroups, but was significantly correlated with the first and second dimension of the factor analysis, the latter lending genetic support to our subdivision. Taken together, these findings suggest a complex relationship between neuropathological subgroups and clinical characteristics, indicating that post-mortem cohort studies are critical to better stratify patients and understand underlying neuropathophysiological mechanisms, in order to ultimately achieve personalised medicine in MS.