We describe here a model of delayed-type hypersensitivity response in the CNS directed against a non-CNS antigen. The results presented in this paper show that bacillus Calmette-Guérin sequestrated behind the blood-brain barrier provokes an immune-mediated assault leading to bystander myelin damage. The delayed-type hypersensitivity response was induced by the intracranial injection of heat-killed bacillus Calmette-Guérin followed by subcutaneous immunization two to six weeks later. A single intracranial injection of bacillus Calmette-Guérin resulted in a rapid myelomonocytic response which persisted for approximately two weeks. By four weeks the inflammatory cells were no longer detected. Serum proteins were also excluded from the CNS parenchyma at this time. However, immunohistochemical staining with anti-bacillus Calmette-Guérin antiserum revealed the presence of bacillus Calmette-Guérin debris at the site of the original intracranial injection, indicating that the inflammatory response failed to clear the mycobacterium fully. Following peripheral sensitization with bacillus Calmette-Guérin in complete Freund's adjuvant, a strong delayed-type hypersensitivity response was detected at the site of bacillus Calmette-Guérin deposits in the CNS. An extensive inflammatory lesion was spread over a large area of the dorsal hippocampus. The lesion was composed predominantly of mononuclear phagocytes and T cells. Staining with anti-myelin basic protein antiserum showed bystander myelin damage. Delayed-type hypersensitivity responses were studied over several months and were still detected in the CNS five months after peripheral immunization.