The generation of new neurons and glia from a precursor stem cell appears to take place in the adult brain. However, new neurons generated in the dentate gyrus decline sharply with age and to an even greater extent in neurodegenerative diseases. Here we raise the question whether peripheral immune mechanisms can generate immunity to such deficits in neuronal repair. We demonstrate that in contrast to primarily innate immunity cytokines, such as interleukin-6 and tumor necrosis factor-, the adaptive immunity cytokine IFN- enhances neurogenesis in the dentate gyrus of adult mice and improves the spatial learning and memory performance of the animals. In older mice, the effect of IFN- is more pronounced in both wild-type mice and mice with Alzheimer’s-like disease and is associated with neuroprotection. In addition, IFN- reverses the increase in oligodendrogenesis observed in a mouse model of Alzheimer’s disease. We demonstrate that limited amounts of IFN- in the brain shape the neuropoietic milieu to enhance neurogenesis, possibly representing the normal function of the immune system in controlling brain inflammation and repair.—Baron, R., Nemirovsky, A., Harpaz, I., Cohen, H., Owens, T., Monsonego, A. IFN- enhances neurogenesis in wild-type mice and in a mouse model of Alzheimer’s disease.