The results of renal cadaver transplants performed between 1984 and 1994 and reported to the Collaborative Transplant Study were analyzed to examine the effect of rejection prophylaxis with OKT3. OKT3 prophylaxis with sequential (i.e., delayed) addition of cyclosporine (CsA), compared with immunosuppressive treatment that included CsA but not OKT3, resulted in a significantly higher overall 3-year graft survival rate in recipients of first transplants (75 +/- 1% vs. 71 +/- 1%, respectively; P < 0.0001) and in recipients of retransplants (68 +/- 2% vs. 62 +/- 1%, respectively; P < 0.001). In contrast, the simultaneous administration of OKT3 and CsA from the first posttransplant day did not result in improved graft survival over treatment with CsA alone. Graft survival rates were significantly associated with matching for HLA-A, -B, and -DR antigens in both first and retransplant recipients treated with a sequential protocol of OKT3/CsA (P < 0.01). Among patients with preformed panel reactive lymphocytotoxic antibodies > 50%, significantly better 3-year graft survival rates were obtained with sequential OKT3/CsA than were achieved without OKT3 in first transplant recipients (80 +/- 5% vs. 63 +/- 1%, respectively; P < 0.001) and in retransplant recipients (73 +/- 5% vs. 58 +/- 1%, respectively; P < 0.01). Significantly improved 3-year graft survival rates with OKT3 and sequential CsA were likewise obtained in two other groups of high-risk patients: black recipients (P < 0.001) and pediatric recipients (P < 0.01). The results demonstrate an advantage for OKT3 prophylaxis in conjunction with delayed CsA therapy among renal transplant recipients at high immunological risk, particularly among presensitized patients.