Significance Narcolepsy with cataplexy is a sleep disorder characterized by excessive daytime sleepiness and sudden loss of muscle tone. These clinical manifestations are the result of selective loss of a neuronal population producing orexin. The etiology of the disease remains elusive, although converging evidence points to a key involvement of the immune system. We developed an animal model to study the autoimmune processes at play in narcolepsy. We demonstrate that cytotoxic CD8 T cells, but not Th1 CD4 cells, are able to target and destroy orexinergic neurons. This selective neuronal loss is responsible for clinical signs mimicking human narcolepsy. By identifying potential immune effectors of the immunopathological process in narcolepsy, these findings offer a rationale for the use of immunotherapies.