Administered proteins are inherently immunogenic, which may influence their efficacy or safety when used therapeutically. A review of the published literature was performed to compare and evaluate the development and consequences of antibodies against therapeutic protein agents for the treatment of multiple sclerosis (MS). Interferon beta (IFNbeta), glatiramer acetate (GA), and natalizumab are all protein-based therapeutic agents approved to treat MS and are associated with the development of antibodies. Both binding antibodies and neutralizing antibodies (NAbs) develop to varying degrees in patients treated with any of the formulations of IFNbeta. Comparison between studies is complicated by differences in methods, assays, criteria for determining NAb positivity, treatment duration, and fluctuation of NAb status. Despite these confounding factors, current data indicate that high-titer persistent NAbs may be relevant in terms of their effect on IFNbeta bioavailability and bioefficacy. GA-reactive antibodies developed in a high proportion of GA-treated patients, but the clinical relevance of these antibodies remains to be established. Immunogenicity against natalizumab was associated with reduced efficacy and increased incidence of infusion reactions. Other emerging monoclonal antibody therapeutics have also been associated with the development of antibodies. Experience with generic biosimilars of other protein therapeutics suggests that the immunogenicity of generic biosimilar agents cannot be assumed and must be established for each formulation.