We investigated the association of the antibody response to myelin oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP) with human leukocyte antigen (HLA) class II alleles in 41 patients with sporadic multiple sclerosis (MS) and 12 multiplex MS families. We found significantly increased antibody response to MOG and MBP in MS patients without any difference to asymptomatic relatives. HLA DRB1*04 was associated with IgM reactivity to MOG in MS patients, and DRB1*15 and DRB5 with anti-MOG IgA among asymptomatic relatives. We conclude that antibody responses to MOG and MBP depend on familial background. Moreover, the humoral immune reactivity against MOG is partially under control of certain HLA class II alleles.