Current immunosuppressive regimens in renal transplantation typically include calcineurin inhibitors (CNIs) and corticosteroids, both of which have toxicities that can impair recipient and allograft health. This 1-year, randomized, controlled, open-label, exploratory study assessed two belatacept-based regimens compared to a tacrolimus (TAC)-based, steroid-avoiding regimen. Recipients of living and deceased donor renal allografts were randomized 1:1:1 to receive belatacept-mycophenolate mofetil (MMF), belatacept-sirolimus (SRL), or TAC-MMF. All patients received induction with 4 doses of Thymoglobulin (6 mg/kg maximum) and an associated short course of corticosteroids. Eighty-nine patients were randomized and transplanted. Acute rejection occurred in 4, 1 and 1 patient in the belatacept-MMF, belatacept-SRL and TAC-MMF groups, respectively, by Month 6; most acute rejection occurred in the first 3 months. More than two-thirds of patients in the belatacept groups remained on CNI- and steroid-free regimens at 12 months and the calculated glomerular filtration rate was 8–10 mL/min higher with either belatacept regimen than with TAC-MMF. Overall safety was comparable between groups. In conclusion, primary immunosuppression with belatacept may enable the simultaneous avoidance of both CNIs and corticosteroids in recipients of living and deceased standard criteria donor kidneys, with acceptable rates of acute rejection and improved renal function relative to a TAC-based regimen.