Belatacept is a first-in-class co-stimulation blocker in development for primary maintenance immunosuppression. A Phase II study comparing belatacept with cyclosporine (CsA) for prevention of acute rejection and protection of renal function in kidney transplant recipients demonstrated similar efficacy and significantly higher measured GFR at 1 year for belatacept, but the incidence of posttransplantation lymphoproliferative disorder was higher. Here, we present the results for the extension of this trial, which aimed to assess long-term safety and efficacy of belatacept. Seventy-eight of 102 patients who were receiving belatacept and the 16 of 26 who were receiving CsA completed the long-term extension period. GFR remained stable in patients who were receiving belatacept for 5 years, and the incidences of death/graft loss or acute rejection were low. The frequencies of serious infections were 16% for belatacept and 27% for CsA, and neoplasms occurred in 12% of each group. No patients who were treated with belatacept and one patient who was treated with CsA developed posttransplantation lymphoproliferative disorder during the follow-up period. Serious gastrointestinal disorders occurred more frequently with belatacept (12% belatacept versus 8% CsA), and serious cardiac disorders occurred more frequently with CsA (2% belatacept versus 12% CsA). Pharmacokinetic analyses showed consistent exposure to belatacept over time. CD86 receptor saturation was higher in patients who were receiving belatacept every 4 weeks (74%) compared with every 8 weeks (56%). In conclusion, this study demonstrated high patient persistence with intravenous belatacept, stable renal function, predictable pharmacokinetics, and good safety with belatacept over 5 years.