The impact of neutralizing antibodies (NAbs) to interferon-beta (IFN-beta) on clinical and imaging parameters in multiple sclerosis (MS) is reviewed. An effect on relapse rates and imaging parameters was noted in patients who tested positive for NAbs, but disability measures were unaffected or showed a trend toward improvement. Patients who developed NAbs during treatment with IFN-beta1a tended to remain NAb+, whereas those who developed NAbs during IFN-beta1b treatment tended to revert to NAb- over time. NAbs were more persistent in patients with high titers. The prevalence of NAbs was lower when a higher-than-standard dose of IFN-beta1b was given in a dose-comparison study. The prevalence of NAbs in an observational study of MS patients who exhibited suboptimal treatment responses to IFN-beta1b was significantly less than the reported prevalence in clinical trials. An immunoregulatory effect of immune complexes of cytokine and anticytokine antibodies is proposed to account for the variability of clinical responses seen in patients who develop NAbs to IFN-beta1b.