Spinal cord injury (SCI) causes the release of danger signals by stressed and dying cells, a process that leads to neuroinflammation. Evidence suggests that inflammation plays a role in both the damage and repair of injured neural tissue. We show that microglia at sites of SCI rapidly express the alarmin interleukin (IL)-1 alpha, and that infiltrating neutrophils and macrophages subsequently produce IL-1 beta. Infiltration of these cells is dramatically reduced in both IL-1 alpha(-/-) and IL-1 beta(-/-) mice, but only IL-1 alpha(-/-) mice showed rapid (at day 1) and persistent improvements in locomotion associated with reduced lesion volume. Similarly, intrathecal administration of the IL-1 receptor antagonist anakinra restored locomotor function post-SCI. Transcriptome analysis of SCI tissue at day 1 identified the survival factor Tox3 as being differentially regulated exclusively in IL-1 alpha(-/-) mice compared with IL-1 beta(-/-) and wild-type mice. Accordingly, IL-1 alpha(-/-) mice have markedly increased Tox3 levels in their oligodendrocytes, beginning at postnatal day 10 (P10) and persisting through adulthood. At P10, the spinal cord of IL-1 alpha(-/-) mice showed a transient increase in mature oligodendrocyte numbers, coinciding with increased IL-1 alpha expression in wild-type animals. In adult mice, IL-1 alpha deletion is accompanied by increased oligodendrocyte survival after SCI. TOX3 overexpression in human oligodendrocytes reduced cellular death under conditions mimicking SCI. These results suggest that IL-1 alpha-mediated Tox3 suppression during the early phase of CNSinsult plays a crucial role in secondary degeneration.