The impact of a prednisone-free immunosuppressive regimen was evaluated in simultaneous pancreas–kidney (SPK) recipients. Patient and graft survivals, rejection rates and the incidence of CMV disease were determined. Two hundred consecutive SPK transplant recipients received tacrolimus-based immunosuppression with (n = 100) or without (n = 100) chronic prednisone therapy. Patients were induced with lymphocyte depleting antibodies or IL-2 receptor blockers and received prophylactic antiviral therapy. Patient and graft survivals and rejection rates were not statistically significantly different between treatment groups. Two-year cumulative incidence of CMV in recipients in the prednisone-free protocol was reduced (7.2% vs. 16%; p = 0.15). Considering only recipients at highest risk (D+/R− or D+R+), incidence of CMV disease in the prednisone-free group (n = 61) compared to the steroid-treated group (n = 48) was reduced from 36% to 18% (p < 0.05). Multivariate analysis confirmed the independent effect of prednisone treatment on the incidence of CMV (RR 2.3; p = 0.04). In the prednisone-free protocol, incidence of CMV was less frequent in recipients receiving induction with Campath versus rabbit antilymphocyte globulin (2.4% vs. 12.6%; p = 0.14). Eliminating prednisone immunotherapy did not adversely affect outcomes and was associated with a reduced rate of CMV in SPK recipients of organs from sero-positive donors.