Background.A phase I study of anti-CD4 immunosuppression of cadaver donor renal allograft recipients was conducted by the NIH Cooperative Clinical Trials in Transplantation to assess safety, tolerability, immunoactivity, and pharmacokinetics of multiple infusions of murine anti-human CD4 monoclonal antibody OKT4A.Methods.Thirty patients were enrolled (August 1992 to October 1993) and received OKT4A at dosages of 0.5 mg/kg (24 patients), 1.0 mg/kg (3 patients), and 2.0 mg/kg (3 patients), beginning and continuing for 12 consecutive days with a standard regimen of cyclosporine, azathioprine, and prednisone. OKT4A treatment was continued after surgery if serum creatinine 24 hr after transplantation was <85% of pretransplantation baseline creatinine.Results.Ninety-three percent of patients treated at 0.5 mg/kg OKT4A and all patients at higher doses had mean peak CD4 saturations in excess of 90%. A human anti-mouse antibody response of >3 times pretreatment levels was observed in 84% of patients. There was no evidence of CD4 T cell depletion. OKT4A was well tolerated without first-dose side effects. For the 19 eligible patients treated with 0.5 mg/kg OKT4A with initial graft function, the 3-month treated rejection rate was 37%. The 2-year graft survival rate for all 30 patients enrolled was 83%, and for the 19 eligible patients, 95%.Conclusions.The high percentage of CD4 saturation, the minimal side effects, the observation of a low 3-month rejection rate, and an excellent 2-year graft survival rate in patients treated with 0.5 mg/kg OKT4A support the continued investigation of an anti-CD4 approach to immunosuppressive therapy.