Data of long-term immunosuppressive protocol comparison are lacking. The goal of this study was to compare kidney transplant outcome using three common immunosuppressive protocols. A retrospective study was performed of the graft and recipient survival using US Renal Data System data (n ؍ 31,012) between January 1, 1995, and December 31, 1999, with the follow-up through December 31, 2000, on prednisone ؉ cyclosporine ؉ mycophenolate mofetil (PCM; n ؍ 17,108), prednisone ؉ tacrolimus ؉ mycophenolate mofetil (PTM; n ؍ 7225), or prednisone ؉ cyclosporine ؉ azathioprine (PCA; n ؍ 6679). Compared with PCM, there is an increased risk for allograft failure associated with PTM (hazard ratio [HR] 1.09; P < 0.05) and PCA (HR 1.15; P < 0.001). Similar associations were demonstrated in the following subgroups: Early (before 1997) and late (in or after 1997) transplant periods, in living-donor transplants, and in adult and kidney-only recipients. This association also was found between PCA regimen and graft survival in the entire patient population (HR 1.15; P < 0.001) and in the studied subgroups. PCA (HR 1.15; P < 0.005), but not PTM (HR 1.01; P ؍ 0.816), regimen was associated with increased recipient mortality in the entire patient population and in patient subgroups. Secondary outcomes (serum creatinine values at given time points, acute rejection rate, and posttransplantation malignancies) are also discussed. These data suggest that a PCM regimen is associated with lower risk for graft failure compared with a PTM regimen and with lower risk for graft failure and recipient death compared with a PCA regimen.