Feline leukemia virus (FeLV) infection is associated with distinct neoplastic, hematologic, and immunosuppressive diseases. Here we report on a novel neurologic syndrome in 16 cats infected with FeLV for more than 2 years. Clinical signs consisted of abnormal vocalization, hyperesthesia, and paresis progressing to paralysis. The clinical course of affected cats involved gradually progressive neurologic dysfunction invariably resulting in euthanasia. Microscopically, white-matter degeneration with dilation of myelin sheaths and swollen axons was identified in the spinal cord and brain stem of affected animals. Neither neoplastic nor hematologic diseases commonly associated with FeLV infection were present. Fungal and protozoal infection in one animal was suggestive of impaired immune competence. Immunohistochemical staining of affected tissues revealed consistent expression of FeLV p27 antigens in neurons, endothelial cells, and glial cells. Furthermore, proviral DNA was amplified from multiple sections of spinal cord as well as intestine, spleen, and lymph nodes. These findings suggest that in a proportion of chronically FeLV-infected cats, a virus evolved with cytopathic potential for cells in the central nervous system.