Objective Neuronal loss, a key substrate of irreversible disability in multiple sclerosis (MS), is a recognized feature of MS cortical pathology of which the cause remains unknown. Fibrin(ogen) deposition is neurotoxic in animal models of MS, but has not been evaluated in human progressive MS cortex. The aim of this study was to investigate the extent and distribution of fibrin(ogen) in progressive MS cortex and elucidate its relationship with neurodegeneration. Methods A postmortem cohort of pathologically confirmed MS (n = 47) and control (n = 10) cases was used. The extent and distribution of fibrin(ogen) was assessed and related to measures of demyelination, inflammation, and neuronal density. In a subset of cases (MS, n = 20; control, n = 10), expression of plasminogen activator inhibitor 1 (PAI‐1), a key enzyme in the fibrinolytic cascade, was assessed and related to the extent of fibrin(ogen). Results Motor cortical fibrin(ogen) deposition was significantly over‐represented in MS compared to control cases in all compartments studied (ie, extracellular p = 0.001, cell body p = 0.003, and neuritic/glial‐processes p = 0.004). MS cases with high levels of extracellular fibrin(ogen) had significantly upregulated PAI‐1 expression in all cortical layers assessed (p < 0.05) and reduced neuronal density (p = 0.017), including in the functionally‐relevant layer 5 (p = 0.001). Interpretation For the first time, we provide unequivocal evidence that fibrin(ogen) is extensively deposited in progressive MS motor cortex, where regulation of fibrinolysis appears perturbed. Progressive MS cases with severe fibrin(ogen) deposition have significantly reduced neuronal density. Future studies are needed to elucidate the provenance and putative neurotoxicity of fibrin(ogen), and its potential impact on clinical disability. Ann Neurol 2017;82:259–270