The final pathway of myelin destruction in immune-mediated demyelination is phagocytosis by macrophages. As part of a systematic study of mechanisms of myelin-oligodendrocyte injury, we have used an in vitro approach to investigate interactions between rat oligodendrocytes and macrophages in order to identify the conditions under which macrophages adhere to and damage oligodendrocytes. No adherence was seen when macrophages alone were co-cultured with homologous oligodendrocytes. However, macrophage attachment to oligodendrocytes was triggered not only by antibody to the major cell-surface component galactocerebroside, but also by antibody to the quantitatively minor antigen, myelin-oligodendrocyte glycoprotein; immunocytochemical observations suggested that phagocytosis of myelin antigen also occurred. No such changes were seen in the presence of an irrelevant (anti-progesterone) antibody, or in the presence of activated complement. These results emphasize that a variety of antibodies, including those to minor myelin-oligodendrocyte antigens, may play a significant role in the development of demyelinated lesions.