S ystemic administration of antigen/peptide for peripheral T cell tolerance has long been investigated as a potential approach to therapy of autoimmune diseases. The multiple antimyelin T cell reactivities likely to be associated with multiple sclerosis (MS) impose major difficulties in devising such an immune-specific therapeutic approach to the disease, because targeting T cells specific for a single autoantigen/epitope is unlikely to be sufficiently effective. Here, we present a pilot study on the possibility of concomitantly inhibiting multiple potentially pathogenic antimyelin T cell reactivities by tolerogenic administration of an artificial “multiantigen/multiepitope” protein. A synthetic gene was constructed to encode selected disease-relevant epitopes of myelin basic protein (MBP), proteolipid protein (PLP), and myelin oligodendrocyte glycoprotein (MOG). The protein product, hmTAP (synthetic human multitarget autoantigen protein), was adequately processed for antigenic presentation of the relevant integral epitopes, in vitro and in vivo. Systemic administration of hmTAP not only suppressed and treated experimental autoimmune encephalomyelitis (EAE) initiated by autoreactivity to a PLP epitope, but also abrogated complex EAE transferred by multispecific line T cells reactive against encephalitogenic epitopes of MBP, PLP, and MOG. These data indicate that multiantigen/multiepitope–directed therapy of complex autoimmune diseases is effective and can be mediated by the protein product of a specifically designed synthetic gene.