Relapsing-remitting experimental autoimmune encephalomyelitis (EAE), a multiple sclerosis model, is induced in mice by injection of myelin proteolipid protein (PLP) encephalitogenic peptide, PLP139-151, in adjuvant. In this study, prior to EAE induction, mice were vaccinated with a bacterial plasmid encoding a PLP-ubiquitin fusion (pCMVUPLP). During the relapse phase of EAE, clinical signs, histopathologic changes, in vitro lymphoproliferation to PLP139-151 and interferon-gamma levels were reduced in pCMVUPLP-vaccinated mice, compared to mock-vaccinated mice (controls). Lymphocytes from pCMVUPLP-vaccinated mice produced interleukin-4, a cytokine lacking in controls. Thus, pCMVUPLP vaccination can modulate the relapse after EAE induction.