Autoimmune NZB/NZW mice were treated with weekly injections of monoclonal antibody (mAb) to L3T4, an antigen expressed on a distinct subpopulation of T cells that respond to class II major histocompatibility antigens. Treatment with anti-L3T4 depleted circulating target cells, reduced autoantibody production, retarded renal disease, and prolonged life relative to control mice treated either with saline or with purified nonimmune rat IgG. These findings establish that autoimmune disease in NZB/NZW mice is regulated by T cells. In contrast to mice treated with nonimmune rat IgG, mice treated with rat anti-L3T4 mAb developed little or no antibody to rat Ig. Thus, the benefits of treatment with anti-L3T4 were achieved while minimizing the risks associated with a host immune response to therapy. This study raises the possibility that treatment with mAb against Leu-3/T4, the human homologue for L3T4 might be effective in the treatment of certain autoimmune diseases in people.