Myelin oligodendrocyte glycoprotein (MOG) is found to induce both autoreactive T-cell and antibody responses associated with demyelinating pathology and is implicated in the pathogenesis of multiple sclerosis (MS). In this study, we addressed the potential association of anti-MOG immune responses with MS by examining, comparatively, both the T-cell and antibody responses to recombinant MOG fragments in MS patients and healthy subjects. T cells recognizing MOG were detected in MS patients as well as in healthy subjects, and their precursor frequency in the blood was not increased in patients with MS. MOG-reactive T cells isolated from both MS patients and healthy subjects exhibited a similar cytokine profile, producing interleukin (IL)-4, IL-10 and tumour necrosis factor (TNF), but not interferon-gamma (IFN-gamma), and recognized predominantly the extracellular (residues 1-60) and the transmembrane/cytoplasmic (residues 154-218) domains of MOG. In contrast, anti-MOG antibodies derived from MS patients displayed a skewed reactivity pattern, even though the occurrence and titres of serum anti-MOG antibodies were only slightly elevated in MS patients. MS-derived autoantibodies were predominantly directed at the 1-60 region of MOG, while naturally occurring anti-MOG antibodies derived from healthy individuals reacted selectively to the 154-218 domain. These differences were statistically significant. The findings of this study are consistent with the presence of anti-MOG antibodies within demyelinating lesions of MS and their role in the induction of demyelinating pathology in animal models. The study has important implications in the understanding of the autoimmune processes in MS.