Previous research has demonstrated a myelin basic protein (MBP) antibody cascade in cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients. The purpose of this study was to determine whether primary antibodies to MBP (anti-MBP) reacted similarly with homologous (human) and heterologous (bovine and porcine) MBP. Myelin basic protein was prepared from central nervous system white matter of humans as well as bovine and porcine species. Immunoglobulin G (IgG) was purified by protein A-Sepharose affinity chromatography from concentrated CSF of MS patients with active or inactive disease or from non-MS controls. Antibodies to MBP were isolated from purified CSF IgG of MS patients with acute relapses by two-step antigen specific (MBP-Sepharose) affinity chromatography. Anti-MBP in the context of whole CSF, in purified CSF-IgG or as purified antibody, reacted identically with homologous and heterologous MBP. Kinetic studies of anti-MBP titers demonstrated that when anti-MBP was reacted in vitro with increasing amounts of homologous or heterologous MBP, the antibody was equally neutralized by either antigen. Neutralization of anti-MBP by homologous and heterologous MBP or their synthetic peptides may also be possible in vivo as a potential therapeutic tool.