BACKGROUND The incidence of acute rejection is considered to be higher after simultaneous pancreas-kidney (SPK) transplantation as compared to renal transplant alone. Therefore, the majority of SPK transplant recipients commonly receive a combination of cyclosporine (CsA) or tracolimus, and azathioprine or mycophenolic mofetyl, corticosteroids and/or antilymphocyte preparations. This study was designed to compare two immunosuppressive protocols for the prevention of acute rejection in patients undergoing SPK transplantation. The primary end-point was the incidence of acute rejection during the first 12 months after transplantation METHODS Fifty patients with type-I insulin-dependent diabetes and chronic renal failure were randomized to receive a triple drug immunosuppressive regimen including CsA, azathioprine and corticosteroids (N = 25), or the quadruple sequential combination of rabbit antithymocyte globulin (ATG) given for 10 days, azathioprine, corticosteroids and delayed CsA (N = 25). Maintenance immunosuppression (CsA and azathioprine, without corticosteroids) was similar in both arms. RESULTS The average follow-up was 36 months in both groups (range 9 to 60 months). No patient was excluded from the study. Although the percentage of patients with adverse events was higher in the ATG group (80 vs. 40%, P < 0.01), none of them resulted in premature discontinuation of the drug. Patients receiving ATG experienced a lower incidence (36% vs. 76%, P < 0.01) and number (13 vs. 29, P < 0.05) of acute renal rejection episodes. However, no difference was observed in patient, pancreas and kidney survival rates between groups. No case of isolated pancreas rejection was observed. CONCLUSIONS The quadruple sequential combination ATG, azathioprine, corticosteroid and CsA significantly reduced the one year incidence of acute renal rejection after SPK transplantation, compared to a triple immunosuppressive regimen.