After damage to the central nervous system (CNS) the body is protected by an adaptive immune response which is directed against myelin-associated proteins. Active immunization with nonpathogenic derivatives of CNS-associated peptides (DCAP) reduces the degeneration of neurons and promotes motor recovery after spinal cord injury (SCI) in rats. In order to improve even more the neurological outcome obtained with this therapy, either a combination of DCAP immunization plus glutathione monoethyl ester (GSHE) or a double DCAP immunization were performed. GSHE is a cell-permeant derivative of glutathione, a potent antioxidant agent that significantly inhibits lipid peroxidation after SCI. After a contusive or compressive SCI, the combination of GSHE + DCAP immunization, induced better motor recovery, a higher number of myelinated axons and better rubrospinal neuron survival than immunization alone. On the other hand, double-DCAP immunization counteracted the protective effect of DCAP therapy. Motor recovery and neuronal survival of double-immunized rats were similar to those observed in control animals (PBS-treated). Further studies revealed that double immunization was not encephalitogenic but inhibited the proliferative response of T-cells specific to the DCAP-immunized peptide. This clonal dysfunction was probably secondary to anergy. GSHE improves the protective effect induced by DCAP immunization while double immunization, reverts it.