We have studied the effects of various monoclonal antibody (MAb) infusions in patients with chronic progressive multiple sclerosis in the hope of developing an immunologically specific, nontoxic form of therapy for this disease. The immunologic responses to anti-T12, anti-T4, and anti-T11 MAb infusions were assessed in subjects with chronic progressive multiple sclerosis as part of phase I clinical studies. It was found that in vivo anti-T-cell MAb infusions specifically suppress in vitro measurements of the human immune response: anti-T11 MAb decreased T-cell activation by phytohemagglutinin, and anti-T4 MAb infusions abolished pokeweed mitogen-induced immunoglobulin synthesis without lysis of the CD4 + T-cell subpopulations. With repeated infusions of the anti-T11 MAb, anti-mouse antibodies were found in the circulation. Although most of the human anti-mouse antibody was not isotype-specific, significant anti-idiotypic activity was observed after repeated infusions in two of three subjects. The human anti-mouse antibodies were almost exclusively of the IgG isotype. The magnitude of the human anti-mouse response was significantly less after administration of either anti-T11 or anti-T4 as compared with anti-T12 MAbs. Murine anti-T-cell MAb can provide a specific, benign form of acute immunosuppression in humans. Repeated administration of these reagents in more chronic diseases can result in anti-idiotypic antibodies that block binding of the anti-T-cell MAbs to the T-cell surface. While the clinical usefulness of currently used murine MAbs in chronic diseases is restricted by the development of human anti-mouse antibodies, newer, more immunosuppressive MAbs may eliminate this problem.