Multiple sclerosis (MS) is an autoimmune disease in which inflammatory lesions lead to tissue injury in the brain and/or spinal cord. The specific sites of tissue injury are strong determinants of clinical outcome in MS, but the pathways that determine whether damage occurs in the brain or spinal cord are not understood. Previous studies in mouse models of MS demonstrated that IFN-γ and IL-17 regulate lesion localization within the brain; however, the mechanisms by which these cytokines mediate their effects have not been identified. In the present study, we show that IL-17 promoted, but IFN-γ inhibited, ELR+ chemokine–mediated neutrophil recruitment to the brain, and that neutrophil infiltration was required for parenchymal tissue damage in the brain. In contrast, IFN-γ promoted ELR+ chemokine expression and neutrophil recruitment to the spinal cord. Surprisingly, tissue injury in the spinal cord did not exhibit the same dependence on neutrophil recruitment that was observed for the brain. Our results demonstrate that the brain and spinal cord exhibit distinct sensitivities to cellular mediators of tissue damage, and that IL-17 and IFN-γ differentially regulate recruitment of these mediators to each microenvironment. These findings suggest an approach toward tailoring therapies for patients with distinct patterns of neuroinflammation.