OBJECTIVE: Prominent inflammation with formation of ectopic B-cell follicle-like structures in the meninges in secondary progressive multiple sclerosis (MS) (SPMS) is associated with extensive cortical pathology and an exacerbated disease course. Our objective was to evaluate the cellular substrates of the cortical damage to understand the role of meningeal inflammation in MS pathology. METHODS: Using >600 tissue blocks from 37 cases of SPMS and 14 non-neurological controls, we carried out a detailed quantitative analysis of cortical atrophy and layer-specific changes in cell populations in SPMS cases with (F(+) SPMS) and without (F⁻ SPMS) B-cell follicle-like structures. RESULTS: B-cell follicle-like structures were detected in the inflamed meninges of 20 of 37 SPMS cases (54%) and were associated with increased subpial cortical demyelination and cortical atrophy. A clear gradient of neuronal loss was observed in grey matter lesions and normal-appearing grey matter in the motor cortex of F(+) SPMS cases. The density of pyramidal neurons was significantly reduced in layers III and V of the motor cortex. Neuronal loss was accompanied by glia limitans damage with astrocyte loss and an opposite gradient of increased density of activated microglia. No gradient of neuronal loss was seen in F⁻ SPMS cases. INTERPRETATION: We demonstrate substantial cortical neurodegeneration and generalized cell loss in progressive MS in association with meningeal inflammation and lymphoid tissue formation, supporting the hypothesis that cytotoxic factors diffusing from the meningeal compartment contribute to grey matter pathology and the consequent increase in clinical disability.