We sought to determine whether combinations of glatiramer acetate and parenteral or ingested type I interferon were synergistic in experimental autoimmune encephalomyelitis. Glatiramer acetate, subcutaneous murine interferon-alpha, or ingested murine interferon-alpha individually improved clinical scores. In contrast, glatiramer acetate in conjunction with either subcutaneous or ingested interferon-alpha did not improve clinical scores compared with control. These data suggest that clinical trials designed to test a possible synergistic effect of glatiramer acetate and type I interferon in humans should be designed to detect possible adverse effects of this combination of immunomodulatory agents.