Acute rejection (AR) superimposed upon delayed graft function (DGF) following renal transplantation worsens graft outcomes. However, risk factors for AR in patients displaying DGF remain unclear. In this study, 71 patients displaying DGF >/= 5 d were investigated. All received cyclosporine, adjunctive azathioprine or mycophenolate mofetil (MMF), and corticosteroids, with 43 receiving anti-CD25 monoclonal antibody induction. AR episodes were seen in 20 of 71 (28%) patients. Higher C2 levels at days 3 and 5 and the use of MMF were associated with a reduced incidence of AR, with increased HLA-DR mismatch associated with an increased risk for AR. C2 levels at days 3 and 5 below 885 and 1096 ng/mL, respectively, showed best discriminatory values for AR. C2 levels showed no correlation with DGF duration. This study suggests that optimizing immunosuppression in patients with DGF (by ensuring adequate calcineurin inhibitor exposure and the use of potent adjunctive immunosuppression) may reduce the incidence of AR without prolonging the duration of dialysis requirement.