In 2-mo-old Lewis rats immunized with bacterial lipopolysaccharides (LPS) precomplexed to guinea pig myelin basic protein (BP), the clinical and histologic manifestations of experimental allergic encephalomyelitis (EAE) were diminished compared with BP-treated controls. Similarly, in animals immunized with BP and challenged with BP-LPS at the same time or as long as 5 days after, the immunization with BP also inhibited the disease. That this capacity to reduce the incidence of BP-induced EAE is a unique property of LPS was suggested by the fact that other negatively charged molecules, such as DNA, RNA, and dextran sulphate, were not effective in inhibiting the clinical signs of EAE. After recovery from EAE induced by BP, some animals develop a recurrence of the disease if challenged with BP at appropriate intervals. However, after recovery from mild EAE induced by BP-LPS and after challenges with EAE-initiating BP antigens, secondary EAE was inhibited significantly.