ABSTRACT: A potential obstacle to successful gene therapy for some patients is the in vivo production of neutralizing antibodies against the recombinant therapeutic product delivered. This is a problem inherent to all gene therapy methods, regardless of the vector used to deliver the protein. This clinical situation can be mimicked in animal models by delivering a foreign protein (i.e., a human protein) to the animal to provoke anti‐human protein antibody production. The efficacy of different immunosuppressive treatments to inhibit the development of neutralizing antibodies can then be investigated. The immunosuppressive agents examined here include drugs (e.g., cyclophosphamide, FK506), cytokines (e.g., interferon‐γ, interleukin‐12), and monoclonal antibodies (e.g., anti‐CD4, anti‐gp39, CTLA4‐Ig). It has been found that a high level of antibody suppression is necessary to allow prolonged delivery of a foreign protein. Immunosuppressive agents capable of this high level of suppression will be important adjuncts to prevent treatment failures in situations where patients are at risk of developing neutralizing antibodies.