Interleukin-1β (IL-1β) is a crucial cytokine in inflammation processes and has been implicated in the pathogenesis of several chronic inflammatory diseases. Strategies designed to blocking IL-1β by passive administration of inhibitors (mAbs, IL-1 receptor antagonist) have previously demonstrated efficacy in rheumatoid arthritis (RA). Using molecular modelling, we have defined three murine IL-1β peptide regions characterized by their close proximity to the receptor. Synthetic peptides corresponding to these regions, in cyclic and linear form, were delivered as immunogens in Swiss mice, resulting in significant levels of autoantibodies directed against the native murine IL-1β cytokine as determined by ELISA and by an assay for neutralization of IL-1β biological activity. More importantly, one of the cyclic peptides showed a protective effect against inflammation and articular destruction in DBA/1 mouse collagen-induced arthritis, a model of RA. The high rate of success observed for active immunization against cytokine peptides in vivo suggests that the in silico approach to autoantigen design may be a promising avenue for the development of anti-cytokine immunotherapeutics.