We investigated the effect of oral administration of type I interferon (IFN) in experimental allergic neuritis (EAN) in Lewis rats immunized with bovine peripheral nerve myelin. Starting at 7 days preceding immunization, rats were fed daily until sacrifice either with 5000 U rat IFN-alpha/beta or mock-IFN. The clinical severity of EAN was significantly reduced in IFN-alpha/beta fed animals compared to mock-IFN fed controls. Demyelination, but not inflammation, was decreased in IFN-alpha/beta fed compared to mock-IFN fed rats at day 20 after immunization. In situ IFN-gamma production and inflammation were reduced when evaluated by immunocytochemistry at day 13 after immunization. Spleen cells from IFN-alpha/beta fed compared to mock-IFN fed EAN rats showed significantly reduced proliferation to stimulation with Con A or peripheral nerve myelin. IFN-gamma production in draining lymph node cells was significantly reduced after stimulation with bovine peripheral nerve myelin. Our data suggest that oral administration of IFN-alpha/beta reduces the severity of EAN, possibly by a reduction in IFN-gamma production.