BACKGROUND: Belatacept is a first in-class co-stimulation blocker developed for primary maintenance  immunosuppression following renal transplantation. Data is widely available comparing belatacept to cyclosporine, limited data is available comparing it with other immunosuppressants. OBJECTIVES: Estimate belatacept's efficacy and safety relative to tacrolimus. METHODS: A systematic review was conducted of randomised controlled trials (RCTs) published between January 1990 and September 2010. Data extraction captured study duration, quality, baseline data, treatment and clinical outcomes. Efficacy and safety outcomes included glomerular filtration rate (GFR), graft- and patient-survival, and acute rejection (AR). The data were analysed with fixed- and random-effects models. Linear models with outcome of mean difference were applied for GFR because GFR (ml/min) is a continuous measure, unlike the other variables which are dichotomous in nature. Logistic models were used for these other outcomes (summary measure being odds ratios). Sensitivity analyses (SAs) were conducted based on trial durations and sub-populations. RESULTS: We identified twenty-six RCTs comparing cyclosporine with tacrolimus, three RCTs comparing cyclosporine with belatacept, and no trials comparing tacrolimus with belatacept. Most trials were 12 months in duration (range: 6 to 60 months). MTC results using 36 month belatacept data suggested benefits with belatacept on patient survival (OR=0.62 95%CI: 0.31,1.24), and difference in GFR (8.50 ml/min/1.73 m2; 95% CI (- 4.22,20.44), versus tacrolimus, with AR outcomes favouring tacrolimus (OR=2.43; 95%CI 1.08,5.34). MTC results indicated reduced graft-survival with belatacept at 36 months (OR=1.18 95%CI: 0.51,2.85). However, SAs using data at 12 months post-transplant demonstrated a benefit for belatacept on graft-survival (OR=0.89 95%CI: 0.36,2.16). Benefits on graft-survival were also seen at 12 and 24 months in the standard-criteria donor population. SAs on the other outcomes resulted in similar conclusions to those of the base case. CONCLUSIONS: Belatacept showed improved renal function and benefits in graft- and patient-survival in comparison to tacrolimus despite increased risks for AR.