Protein- and peptide-based disease-modifying agents for multiple sclerosis (MS), including interferon beta (IFNbeta) and glatiramer acetate (GA), have been associated with the formation of antibodies. Neutralizing antibodies (NAbs) block or neutralize the biological effects of the protein or polypeptide, potentially decreasing the therapeutic effects of these agents. Although the clinical relevance of antibodies against GA requires further investigation; both the incidence of NAbs to the three IFNbeta products (IFNbeta1b-Betaseron, IFNbeta1a-Rebif, and IFNbeta1a-Avonex) and the clinical relevance are quite clear. Data from clinical trials of IFNbeta products show that the immunogenicity of Betaseron > Rebif > Avonex and persistent NAbs reduce the clinical efficacy of IFNbeta. Because the initial detection of NAbs in the serum of patients receiving IFNbeta usually occurs between 6 and 15 months and appears to precede any apparent reduction in clinical efficacy by approximately 6 to 12 months, trials with a duration of less than 3 years are problematic when the clinical impact of NAbs is assessed. The potential development of NAbs is an important consideration in selection and monitoring treatment of MS. Long-term prospective studies are needed to further define the clinical effects of NAbs on patients receiving disease-modifying therapies for MS.