Objective. Many studies have compared the safety and efficacy of the calcineurin inhibitor (CNI) avoidance or CNI withdrawal regimens with typical CNI regimens, but the results remain controversial. The aim of this systematic review and meta-analysis is to make a profound review and an objective appraisal of the safety and efficacy of the CNI avoidance and CNI withdrawal protocols. Methods. We searched PUBMED, EMBASE, and the reference lists of retrieved studies to identify randomized controlled trials (RCTs) that referred to CNI-free regimens, CNI avoidance, or CNI withdrawal for kidney transplantation. Eight publications involving 27 different RCTs and a total of 3953 patients were used in the analysis. Results. Use of mammalian target of rapamycin inhibitors, namely sirolimus (SRL), in combination with mycophenolate, conserve graft function at 1 year (glomerular filtration rage [GFR]: mean difference MD 6.21, 95% CI 0.02-12.41, P = .05; serum creatinine: MD 0.11, 95% CI 0.19 to 0.03, P = .01, respectively) and 2 years post-transplant (GFR: MD 13.96, 95% CI 7.32-20.60, P < .0001). Similarly, early withdrawal (<= 6 months) of CNIs protect graft function at 1 year after transplant (GFR: MD 7.03, 95% CI 4.84-9.23, P < .00001, serum creatinine: MD -0.21, 95% CI -0.22 to -0.19, P < .00001, respectively). CNI avoidance and withdrawal strategies are associated with higher incidence of acute rejection at 1 year post-transplant (odds ratio OR 1.74, 95% CI 1.08-2.81, P = .02; OR 1.78, 95% CI 1.35-2.34, P < .0001, respectively). At 2 years after transplant, there was no significant difference (OR 0.92, 95% CI 0.33-2.51, P = .86; OR 2.42, 95% CI 1.01-5.82, P = .05, respectively). Meanwhile, neither adverse events nor patient/graft survival differed significantly between the CNI-free and CNI protocols at 1 and 2 years. Referring to long-term results in the published RCTs, use of CNI-free and CNI withdrawal regimens achieve better renal function vs CNI regimens, with no significant difference in patient and graft survival, acute rejection, and most reported adverse events. Conclusions. In conclusion, this systematic review and meta-analysis suggests that renal recipients with early withdrawal of CNI drugs or avoiding CNI with SRL perform better to conserve graft function at 1 and 2 years post-transplant. Though the use of CNI regimens performs no better in 2-year acute rejection vs the contrast group, they greatly decrease the incidence of acute rejection at the first year after transplantation. CNI avoidance and