In experimental animal models of multiple sclerosis demyelinating antibody responses are directed against the myelin oligodendrocyte glycoprotein (MOG). We have investigated whether a similar antibody response is also present in multiple sclerosis patients. Using the recombinant human extracellular immunoglobulin domain of MOG (MOG-Ig) we have screened the sera and CSFs of 130 multiple sclerosis patients, 32 patients with other inflammatory neurological diseases (OIND), 30 patients with other non-inflammatory neurological diseases (ONND) and 10 patients with rheumatoid arthritis. We report that 38% of multiple sclerosis patients are seropositive for IgG antibodies to MOG-Ig compared with 28% seropositive for anti-myelin basic protein (MBP). In contrast, OIND are characterized by similar frequencies of serum IgG antibody responses to MOG-Ig (53%) and MBP (47%), whereas serum IgG responses to MOG-Ig are rare in ONND (3%) and rheumatoid arthritis (10%). Anti-MBP IgG antibodies, however, are a frequent finding in ONND (23%) and rheumatoid arthritis (60%). Our results provide clear evidence that anti-MOG-Ig antibodies are common in CNS inflammation. However, in OIND these antibody responses are transient, whereas they persist in multiple sclerosis. We demonstrate that the serum anti-MOG-Ig response is already established in early multiple sclerosis (multiple sclerosis-R0; 36%). In later multiple sclerosis stages frequencies and titres are comparable with early multiple sclerosis. In contrast, the frequency of anti-MBP antibodies is low in multiple sclerosis-R0 (12%) and increases during disease progression in relapsing-remitting (32%) and chronic progressive multiple sclerosis (40%), thus suggesting that anti-MBP responses accumulate over time. Finally we provide evidence for intrathecal synthesis of IgG antibodies to MOG-Ig in multiple sclerosis.