The OX–40 protein was selectively upregulated on encephalitogenic myelin basic protein (MBP)–specific T cells at the site of inflammation during the onset of experimental autoimmune encephalomyelitis (EAE). An OX–40 immunotoxin was used to target and eliminate MBP–specific T cells within the central nervous system without affecting peripheral T cells. When injected in vivo, the OX–40 immunotoxin bound exclusively to myelin–reactive T cells isolated from the CNS, which resulted in amelioration of EAE. Expression of the human OX–40 antigen was also found in peripheral blood of patients with acute graft–versus–host disease and the synovia of patients with rheumatoid arthritis during active disease. The unique expression of the OX–40 molecule may provide a novel therapeutic strategy for eliminating autoreactive CD4⁺T cells that does not require prior knowledge of the pathogenic autoantigen.