Spinal cord injury (SCI) causes delayed secondary biochemical alterations that lead to tissue loss and associated neurological dysfunction. Up-regulation of cell cycle proteins occurs in both neurons and glia after SCI and may contribute to these changes. The present study examined the role of cell cycle activation on secondary injury after severe SCI in rat. SCI caused cell cycle protein up-regulation associated with neuronal and oligodendroglial apoptosis, glial scar formation and microglial activation. Treatment with the cell cycle inhibitor flavopiridol reduced cell cycle protein induction and significantly improved functional recovery versus vehicle-treated controls at 21 and 28 days post-injury. Treatment also significantly reduced lesion volume, as measured by MRI and histology, decreased astrocytic reactivity, attenuated neuronal and oligodendroglial apoptosis and reduced the production of factors associated with microglial activation. Thus, flavopiridol treatment improves outcome after SCI by inhibiting cell cycle pathways, resulting in beneficial multifactorial actions on neurons and glia.