Experimental autoimmune neuritis (EAN), an acute demyelinating inflammatory disease of the peripheral nervous system (PNS), is a good model for the human counterpart, Guillain-Barré syndrome. Apolipoprotein E (ApoE), a 34 kDa glycosylated protein with multiple biological properties, has been linked both with the innate immune response of mice and with neurological disease. The present study investigated the previously unexplored role of ApoE in autoimmune-mediated demyelination. ApoE-deficient (apoE -/-) mice exhibited a greater susceptibility to EAN induced by the PNS myelin P0 protein peptide 180-199, as compared to wild type (apoE +/+) mice. The augmented susceptibility seen in apoE -/- mice was associated with increased inflammatory cell infiltrates in the PNS during the effector phase. Although the 2 groups of mice exhibited no quantitative or proportional differences in splenic lymphocyte populations, the apoE -/- mice showed enhanced antigen-specific proliferation of T cells of spleen, which is related to modified macrophage function, upregulation of Th1 and downregulation of Th2-autoreactive responses to P0 peptide. These effects were shown as increased numbers of IFN-gamma expressing cells in the spleen and of IFN-gamma, IL-12 and TNF-alpha expressing cells in the PNS, as well as a decreased IL-10 production by splenic cells in apoE -/- mice. In addition, apoE -/- mice had enhanced antigen-specific antibody responses, which might have contributed to their aggravated EAN. These data provide strong evidence that apoE acts as an inhibitor of this inflammatory and demyelinating disease by upregulating IL-10, as well as by inhibiting Th1 responses and antigen-specific antibody formation. These data may aid the development of new and more effective therapeutic strategies for inflammatory and demyelinating diseases such as Guillain-Barré syndrome.