In renal transplant recipients (RTRs), a belatacept-based immunosuppressive regimen is associated with beneficial effects on cardiovascular (CV) risk factors compared with calcineurin inhibitor (CNI)-based regimens. The aim of this randomized, multi-national trial was to compare calculated CV risk between belatacept and CNI (predominantly tacrolimus) treatments using a valdidated model developed for RTRs. From 9 transplant centers, RTRs from 3 to 60 months post-transplantation were recruited to either continue treatment with a CNI-based regimen or switch to belatacept. We compared the change in estimated 7-year risk of major adverse cardiovascular events (MACE) and all-cause mortality after 12 months of treatment. In the 105 RTRs randomized, we found no differences between the treatment groups in predicted risk for MACE or mortality. Diastolic blood pressure was lower after belatacept treatment compared with CNI. The mean changes in traditional CV risk factors, including renal transplant function, were otherwise similar in both treatment groups. The belatacept group had four acute rejection episodes; two were severe rejections, of which one led to graft loss. In conclusion, we found no effects on calculated CV risk by switching to belatacept treatment.