To define in more detail the features of the immunoreactive myelin basic protein (MBP) present in cerebrospinal fluid (CSF) of humans following acute injury to central nervous system myelin, the epitopes of MBP recognized by three different antisera, each capable of detecting immunoreactive MBP in CSF, were examined. All three antisera reacted well with human MBP and human MBP peptide 45-89. Only in radioimmunoassays in which the MBP peptide 45-89 served as the radioligand could clearly elevated values of immunoreactive MBP be measured in CSF specimens from 5 patients with multiple sclerosis during or immediately after an exacerbation. The two antisera that reacted well with MBP peptide 80-89 resulted in higher levels of immunoreactive MBP measured in CSF. An epitope present in human MBP peptide 80-89 but sharing a conformation with both MBP and MBP peptide 45-89 is present in CSF following acute central nervous system myelin damage in multiple sclerosis.