From April, 1980 to November, 1988, 163 one or two haplotype-mismatch living related (LR) or living unrelated (LUR) potential renal transplant recipients received three 200 ml aliquots of donor specific transfusion (DST) at biweekly intervals with concomitant azathioprine (2 mg/kg/day). Following transplantation, only prednisone and azathioprine were given for immunosuppression. The results for the DST group are compared with those for HLA identical living recipients (57 patients) transplanted during this same interval (1980-1988). Comparison is also made with a group of one or two haplotype-mismatched living donor recipients (54 patients) not treated with DST but with triple drug therapy (prednisone, azathioprine, cyclosporine) and antithymocyte globulin (ATG) or OKT-3 induction. Permanent T cell crossmatch sensitization occurred in 11 of 163 patients (7%). Successful DST donor transplants were performed between 121 one HLA haplotype-mismatched, 14 two HLA haplotype-mismatched LR, and 7 two haplotype-mismatched LUR pairs. Actual one- and five-year graft survivals were 94%, 100%, 100%, and 72%, 85%, and 71%, respectively, for these three subgroups of DST treated patients. The graft survival for all DST pretreated recipients at one, five, and ten years was comparable to the HLA-identical group (94%, 79%, 64% vs. 91%, 80% and 77%). At a mean follow-up of 10 1/2 years, 54% (80 patients) of the entire group of 147 patients transplanted after DST have functioning transplants with a mean serum creatinine of 1.7 mg/dl. Fifteen percent of DST patients (21 patients) died with a functioning graft 2 to 132 months after transplantation, 26% (37 patients) rejected the DST graft after 1 to 128 months, and 6% (9 patients) were lost for nonimmunological reasons. No lymphoproliferative disease developed in the DST group and the incidence of cytomegalovirus sepsis was only 2% (3 patients). The long-term beneficial effects of DST on renal allograft survival and function and the lower incidence of the complications of nonspecific immunosuppression should encourage increased utilization of DST in renal transplantation.