Multiple sclerosis (MS), a common neurodegenerative disease of the CNS, is characterized by the loss of oligodendrocytes and demyelination. Tumor necrosis factor α (TNF-α), a proinflammatory cytokine implicated in MS, can activate necroptosis, a necrotic cell death pathway regulated by RIPK1 and RIPK3 under caspase-8-deficient conditions. Here, we demonstrate defective caspase-8 activation, as well as activation of RIPK1, RIPK3, and MLKL, the hallmark mediators of necroptosis, in the cortical lesions of human MS pathological samples. Furthermore, we show that MS pathological samples are characterized by an increased insoluble proteome in common with other neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). Finally, we show that necroptosis mediates oligodendrocyte degeneration induced by TNF-α and that inhibition of RIPK1 protects against oligodendrocyte cell death in two animal models of MS and in culture. Our findings demonstrate that necroptosis is involved in MS and suggest that targeting RIPK1 may represent a therapeutic strategy for MS. Display omitted •Caspase-8 activation is defective in pathological samples from MS patients•Insoluble aggregates of RIPK1 and RIPK3 form in human MS cortical lesions•The RIPK1 kinase inhibitor 7N-1 blocks demyelination induced by cuprizone and EAE Using both animal models and human tissue, Ofengeim et al. provide evidence for the involvement of RIPK1 and necroptosis in mediating the deleterious processes in multiple sclerosis (MS) and provide a link between this disease and other neurodegenerative diseases.