Background: Cardiovascular morbidity and mortality associated with calcineurin-inhibitor (CNI) based immunosuppression regimens present the biggest challenge for medium to long-term patient and graft outcomes. Belatacept, a selective T-cell co-stimulation blocker offers the potential for effective CNI-free maintenance. Objectives: To systematically review the benefit and harms of Belatacept versus CNI-based regimens. Search Strategy: We searched databases and conference proceedings to December 2011. Selection Criteria: Randomised controlled trials of Belatacept versus CNIs in kidney transplant recipients. Data Collection and Analysis: Two investigators independently extracted data for study quality and transplant outcomes and synthesized results using random effects meta-analysis, expressed as risk ratios (RR) and mean difference (MD) at 1 year, both with 95% confidence intervals (CI). Stratified analyses and meta-regression were used to investigate potential heterogeneity. Results: We included 4 trials (1516 recipients): 3 studies (1427 participants) compared Belatacept versus Cyclosporine; 1 study (89 participants) compared Belatacept versus Tacrolimus. Co-interventions varied: Basiliximab (3 studies, 1427 participants); Anti-Thymocyte Globulin (1 study, 89 participants); Mycophenolate Mofetil (4 studies, 1490 participants); and Sirolimus (1 study, 26 participants). Belatacept compared to CNI (figure 1) did not increase risk of mortality (RR0.62, CI0.31-1.25), death-censored graft loss (RR0.78, CI0.5-1.22) or acute rejection (RR1.49, CI0.76-2.93). Incidence of new-onset diabetes after transplant (NODAT, RR0.35, CI0.14-0.86), chronic allograft nephropathy (CAN, RR0.72, CI0.55-0.94) and use of multiple anti-hypertensives (RR0.79, CI0.68-0.91) were reduced. There was no difference in incidence of malignancy (RR0.98, CI0.31-3.13).[Fig 1 Belatacept v CNI:Main Outcomes, 1year]Considering dosage; high-dose Belatacept compared to CNI did not increase risk of mortality (RR0.85, CI0.44-1.64), death-censored graft loss (RR0.85, CI0.51-1.42) or acute rejection (RR1.69, CI0.88-3.27). NODAT (RR0.51, CI0.28-0.92) and CAN (RR0.71, CI0.52-0.96) were reduced, with no difference in use of multiple anti-hypertensives (RR0.88, CI0.71-1.09) or malignancy (RR0.92, CI0.24-3.55). Low-dose Belatacept compared to CNI did not increase mortality (RR0.48, CI0.21-1.08), death-censored graft loss (RR0.85, CI0.52-1.39), or acute rejection (RR1.46, CI0.8-2.66). NODAT (RR0.47, 95% CI0.26-0.87), CAN (RR0.72, 95% CI0.55-0.94) and use of multiple anti-hypertensives (RR0.79, 95% CI0.68-0.91) were reduced. Risk of malignancy (RR0.48, CI0.21-1.08) was not different. Comparing high versus low-dose Belatacept, we observed no significant difference in any outcome. Conclusions: For outcomes measured at 1 year, recipient and graft survival are no different, but Belatacept-treated patients use fewer anti-hypertensive agents and have less NODAT. Considerable uncertainty remains about relative effects over the medium term and longer, particularly whether these translate into improved cardiovascular outcomes. Longer-term trial data could better instruct Belatacept's therapeutic application.