Intrathecal antibody production is a hallmark of multiple sclerosis and humoral immunity is thought to play an important role in the inflammatory response and development of demyelinated lesions. The presence of lymphoid follicle-like structures in the cerebral meninges of some multiple sclerosis patients indicates that B-cell maturation can be sustained locally within the CNS and contribute to the establishment of a compartmentalized humoral immune response. In this study we examined the distribution of ectopic B-cell follicles in multiple sclerosis cases with primary and secondary progressive clinical courses to determine their association with clinical and neuropathological features. A detailed immunohistochemical and morphometric analysis was performed on post-mortem brain tissue samples from 29 secondary progressive (SP) and 7 primary progressive (PP) multiple sclerosis cases. B-cell follicles were detected in the meninges entering the cerebral sulci of 41.4% of the SPMS cases, but not in PPMS cases. The SPMS cases with follicles significantly differed from those without with respect to a younger age at multiple sclerosis onset, irreversible disability and death and more pronounced demyelination, microglia activation and loss of neurites in the cerebral cortex. Cortical demyelination in these SPMS cases was also more severe than in PPMS cases. Notably, all meningeal B-cell follicles were found adjacent to large subpial cortical lesions, suggesting that soluble factors diffusing from these structures have a pathogenic role. These data support an immunopathogenetic mechanism whereby B-cell follicles developing in the multiple sclerosis meninges exacerbate the detrimental effects of humoral immunity with a subsequent major impact on the integrity of the cortical structures.