OBJECTIVE: To determine the safety and immunogenicity of an idiotypic anti-dsDNA vaccine in patients with nonactive systemic lupus erythematosus (SLE) and stable lupus nephritis. METHODS: Patients with SLE with a history of nephritis were randomized for vaccination with the murine anti-dsDNA monoclonal antibody (Mab) 3E10 in a dose ranging, double blind, placebo controlled study (phase I). RESULTS: Of the 9 patients injected with Mab 3E10, 5 showed a human anti-mouse antibody (HAMA) response, in large part antiidiotypic, which developed within the first 3 months in 3 strong HAMA responders, and more than one year after immunization in an initially weak HAMA responder. All but one nonresponder were receiving low dose prednisone. No adverse events, in particular no evidence of lupus flares, and no untoward laboratory findings were reported over a followup of 2 years. CONCLUSION: In patients with stable lupus nephritis, immunization with Mab 3E10 appears safe and can generate a significant antiidiotypic response. Idiotypic vaccination may be an approach to specific immunotherapy of autoimmune lupus nephritis.