Tolerance induction to prevent activation of a naïve T-cell repertoire has been well documented in rodents and can be readily achieved by intravenous, oral or intranasal administration of antigen in the absence of adjuvants. In autoimmune diseases such as multiple sclerosis (MS) the presence of an established memory/effector T-cell repertoire against self-antigens is likely to be more relevant than the potential reactivity of naive T cells. Methods to eliminate such an established T-cell response are less well understood. In this study, we explored the effectiveness of intravenous soluble antigen to eliminate a pre-existing T-cell response against αB-crystallin, a candidate autoantigen in MS. We used mice that are deficient for the target antigen. This condition allowed for a vigourous T-cell and antibody response to develop upon immunization, and eliminated all possible endogenous mechanisms of tolerance for αB-crystallin that are found in normal rodents. When applied 3 weeks after priming with αB-crystallin, intravenous administration of soluble antigen almost completely abrogated the established T-cell response in a dose-dependent manner as evidenced by T-cell non-responsiveness in tolerized animals to a re-challenge with antigen in complete Freund's adjuvant. Evaluating delayed-type hypersensitivity responses after tolerance induction revealed that the tolerizing effect was achieved within 24 hr. Furthermore, the tolerizing effect was found to be antigen-specific and long lasting. In contrast, serum antibody levels were markedly increased. Our data clarify that in the absence of any natural form of immune regulation, antigen-specific memory/effector T cells can be effectively silenced by intravenous antigen. © 2007 Blackwell Publishing Ltd.