LEW strain rats received BN strain renal allografts and were treated with daily injections of 100 micrograms BWH-4, a new IgG2a mouse anti-rat CD4 monoclonal antibody, intravenously for 5 to 10 days. These animals had a median actuarial survival of 28 days. Control animals rejected their grafts and died of uremia between day 6 and 8 post transplant. Animals treated with BWH-4 did not suffer acute graft loss and had stable renal function throughout the follow-up period of 5 weeks. Peripheral blood, lymph node, and splenic lymphocytes showed 60-80% decrease in the CD4+ subset which normalized by 4 weeks after transplantation. There was depressed proliferative response of lymph node cells to alloantigen and mitogen which persisted up to 4 weeks after cessation of therapy. Treated animals produced anti-BN antibodies as well as antibodies to the infused BWH-4. There was no correlation, however, between these humoral responses and allograft function. We conclude that low-dose monotherapy with the BWH-4 anti-CD4 monoclonal antibody effects cellular hyporesponsiveness, prevents acute renal allograft rejection, and prolongs survival.