We demonstrate a role for immune functions in the spontaneous remyelination of central nervous system (CNS) axons after lysolecithin-induced demyelination in the spinal cord. Rag-1-deficient mice lack both B cells and T cells and show significantly reduced spontaneous remyelination compared with control mice of matching genetic background. Mice lacking or depleted of either CD4(+) T cells or CD8(+) T cells also exhibit reduced remyelination. These data indicate that T cells are necessary for efficient CNS remyelination. Thus, general nonspecific immunosuppression as a therapeutic approach for the treatment of CNS injury and demyelinating disease may have undesirable effects on subsequent tissue repair.