Interferon-γ(IFN-γ) is a cytokine with multiple activities on a variety of cells. Under various circumstances, IFN-γcan exhibit either pro-inflammatory or inhibitory actions. Treatment of SJL/J mice with a monoclonal antibody (Mab) to IFN-γduring the afferent limb of the immune response to myelin protein produced an enhancement of acute experimental allergic encephalomyelitis (EAE), with increased morbidity, mortality and earlier onset of disease. Systemic administration of IFN-γdid not improve or worsen clinical outcome, but delayed disease onset. Passive transfer of immune lymph node cells co-activated with MBP and anti-IFN-γMab resulted in more severe disease than that induced by MBP stimulated cells or MBP and IFN-γco-stimulated cells. However,in vitroproliferation of an MBP specific T cell line was not influenced by IFN-γnor anti-IFN-γtreatment. Mab to IFN-γinhibited suppressor function, in a non-specific assay. Thesein vivoandin vitroresults suggest that systemic IFN-γserves as a physiological regulator of a suppressor mechanism in EAE. The abrogation of this regulatory mechanism by anti-IFN-γadministration contributes to a more severe form of experimental allergic encephalomyelitis.