We induced a chronic relapsing form of experimental autoimmune encephalomyelitis in 7- to 10-week-old female SJL/J mice using a subcutaneous injection of an emulsion containing syngeneic mouse spinal cord homogenate in phosphate-buffered saline and Mycobacterium tuberculosis (MT) in incomplete Freund9s adjuvant. Following the animals9 recovery from the first attack periods, we fed them varying doses of type I interferon (IFN) or mock IFN three times per week for 6 weeks. This treatment decreased proliferation to guinea pig myelin basic protein and MT compared with control in draining lymph node and diminished inflammation in the CNS. Oral IFN altered the cytokine profile of concanavalin A-activated spleen cells by decreasing IFN-γ secretion. These results suggest that type I IFNs are active by the oral route, have significant clinical and immunomodulatory effects, and can decrease an established and ongoing immune response to sensitized antigens. The oral administration of biologic-response modifiers, such as type I IFNs, provides a potentially nontoxic, convenient, continuous means of delivering immunoactive substances via the gut regional immune system that can alter cytokine production and suppress clinical relapses.