Injection of antigen cross-linked accessory cells has proven to be an efficient and highly selective approach for inducing epitope-specific peripheral tolerance. This approach has been used successfully to inhibit induction of experimental autoimmune encephalomyelitis (EAE) and to dissect the relative dominance of component encephalitogenic determinants that contribute to both acute and relapsing EAE. In this study, we evaluated the tolerogenic effect of the dominant encephalitogenic epitope for S JL/ J mice, residues 13P-151 of myelin proteolipid protein (PLP), on the induction and relapses of EAE induced actively with PLP139-151/CFA. Our results demonstrate the powerful protective effect of treating mice before induction of EAE with PLP139-151-conjugated splenocytes (SPL) on the incidence and severity of both the initial episode and the first relapse of EAE. Moreover, treatment of mice on the first day of onset of clinical signs of EAE reduced the severity of the first relapse, apparently by reducing T cell recognition of PLP139-151, although no significant therapeutic effect was observed during the initial treated clinical episode. These data demonstrate the utility of using neuroantigen-coupled accessory cells to prevent and treat relapsing EAE.