We report a comparative study of the B- and T-cell responses to the extracellular immunoglobulin (Ig)-like domain of human myelin–oligodendrocyte glycoprotein (MOG^Igd) in the blood of patients with multiple sclerosis and healthy controls using a bacterial recombinant human protein (rhMOG^Igd). The frequency of anti-rhMOG^Igd-seropositive samples, as determined by Western blotting, was significantly higher in the multiple sclerosis group (54%) than in normal random controls (excluding laboratory workers exposed to MOG) (22%; P = 0.02). In contrast, there was no difference in rhMOG^Igd-induced proliferation indices of peripheral blood T cells between patients and controls. To characterize the rhMOG^Igd-reactive T-cell repertoire, we isolated a panel of MOG-specific CD4⁺ T-cell lines from multiple sclerosis patients and normal subjects, and these revealed a heterogeneous response with respect to epitope specificity, cytokine response, MHC (major histocompatibility complex) restriction and T-cell receptor Vβ-chain usage. The majority of the T-cell lines recognized epitopes in the N-terminal region of MOG (amino acids 1–60). One epitope (represented by peptide 27–50) was exclusively recognized by T-cell lines from normal controls. Forty per cent of the MOG-specific T-cell lines analysed displayed a Th-2 or Th-0 cytokine profile and could therefore act as helper T cells in vivo.