Glatiramer acetate (GA, Copaxone, copolymer 1) for injection is an approved drug for relapsing-remitting multiple sclerosis. The clinical and immunological effects of GA were extensively studied in experimental autoimmune encephalomyelitis (EAE), the experimental animal model for MS. The effect of oral administration of GA was tested in both rodents and primates in acute as well as in chronic relapsing (CR) models of EAE. Oral GA was found to suppress acute EAE induced in rats, mice, and rhesus monkeys. The effect of GA was also tested in several models of CR-EAE: proteolipid protein and myelin oligodendrocyte glycoprotein induced CR-EAE in mice, CR-EAE in Biozzi mice, and CR-EAE in cynomolgus monkeys. In all the murine models, oral treatment with GA initiated at the peak of first relapse reduced the severity of disease and suppressed further relapses. Suppression of EAE with oral GA was associated with marked inhibition of spleen cell proliferation and Th1 cytokine (IL-2 and IFN-gamma) response to the respective autoantigens. GA-specific T cell lines of the Th2/3 type that inhibit EAE induction in vivo, similarly to those induced by injection of GA, could be isolated from spleens of GA-fed mice and rats. Furthermore, as demonstrated previously for GA-specific cells induced by the parenteral route, the orally induced GA-specific cells accumulate in the CNS and secrete in situ Th2 cytokines in response to both GA and MBP as well as brain-derived neurotrophic factor (BDNF). Although a clinical trial in MS with two doses of oral GA in enteric-coated tablets did not show a significant effect either at the clinical or immunological level, the results presented here suggest that oral GA may still be developed into a therapeutic modality in MS.