This study compared the effects of using two T-cell depleting antibodies, alemtuzumab (anti-CD 52, Campath-1H®) and rabbit antithymocyte globulin (Thymoglobulin®), as induction immunosuppression for recipients of simultaneous pancreas-kidney transplantation given a prednisone-free maintenance regimen. We used a single-center, nonrandomised, retrospective, sequential study design to evaluate the efficacy and safety of alemtuzumab (n = 50) or antithymocyte globulin (n = 38) induction in combination with a prednisone-free, tacrolimus/sirolimus-based immunosuppression protocol. Kaplan-Meier analyses of long-term patient and graft survivals and rejection rates were determined according to induction agent. Secondary endpoints included the quality of renal allograft function, incidence of infectious and malignant complications, and cost considerations. Overall long-term patient and graft survival rates did not significantly differ between patients treated with alemtuzumab and antithymocyte globulin. Rejection rates were also nearly equivalent at 1 and 2 years. Viral infectious complications were statistically significantly lower in the alemtuzumab group. The cost of alemtuzumab induction was lower than antithymocyte globulin. Alemtuzumab induction followed by steroid-free maintenance therapy with a tacrolimus/sirolimus-based immunosuppression regimen provided an effective, safe and cost-conscious approach to SPK transplantation.