Kidney transplantation is usually followed by immunosuppressive therapy to prevent early rejection and prolong graft survival. The calcineurin inhibitors (CNIs) represent the most commonly used agents. However, available evidence suggests the poor outcome over the long term, maybe be due to the potential nephrotoxicity associated with CNIs. Several randomized trials have compared tacrolimus (TAC) with cyclosporine, to find the optimal agent for renal transplantation; however, studies have shown conflicting results. The aim of this study was to systematically review and update the evidence for the benefits and harm of TAC versus cyclosporine as the primary immunosuppression after renal transplantation. The study was a systematic review and meta-analysis. An electronic literature search was conducted to identify appropriated trial studies. The outcomes were presented as relative risk (RR), with 95% confidence intervals (CI). Statistical analysis used was meta-analysis. Twenty-one eligible randomized controlled trials were included in this systematic review. TAC was significantly superior to cyclosporine considering the total effect size of graft loss (RR 0.089; 95% CI0.057-0.122, P <0.001), acute rejection (RR 0.638; 95% CI 0.571-0.713, P <0.001) and hypercholeste-rolemia (RR 0.634; 95% CI, 0.539-0.746, P <0.001). On the contrary, cyclosporine seemed to be significantly superior to TAC with regard to diabetes (RR 1.891; 95% CI 1.522-2.350, P <0.001). However, no significant differences between the two CNIs were found with regard to mortality, infection, and hypertension. The review indicates that TAC is significantly superior to cyclosporine regarding graft loss, acute rejection, and hypercholesterolemia, but cyclosporine seems to be significantly superior to TAC regarding diabetes. However, further large randomized trials are suggested.