We studied 72 consecutive simultaneous pancreas kidney transplant (SPKT) recipients. There were 14 patients with positive pretransplant cross-matches (positive CDC- B cell and/or positive flow T or B cross-match). The control group included all 58 SPKT recipients with a negative crossmatch. The study group received induction with low dose intravenous immunoglobulin (IVIg), rabbit antithymocyte globulin (rATG; total dose 6 mg/kg), or alemtuzumab (30 mg single dose) and maintenance with tacrolimus, mycophenolate mofetil (MMF), and corticosteroids. The control group was treated similarly, but with steroid avoidance and no IVIg. Biopsy-proven acute rejection (BPAR) of the kidney allograft occurred in 7 study patients (50%) compared with 10% in the control group (P = .022). One patient experienced acute cellular rejection (ACR); the other 6 (43%), antibody-mediated rejection (AMR). None of the cross-match negative patients had AMR (P = .001). The mean follow-up period was 18.7 months in the study group, and 18.3 months in the control group. The 1-year actuarial patient survival was 91.7% in the study group and 97% in the control group. Kidney allograft survival was 91.7% in the study group and 95.2% in the control group. Pancreas allograft survival was 76.9% in study group and 89.6% in the control group (P = .088). We concluded that patients with a positive pretransplant CDC-B cross-match and/or positive flow cross-match have an increased risk of AMR; more intensive desensitization is needed with low-dose IVIg and induction with either rATG or alemtuzumab.