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Background: Everolimus is an immunosuppressive agent with a novel mode of action but has a different clinical role with calcineurin inhibitors (CNI). The aim of this study was to evaluate the safety and effectiveness of everolimus compared with sirolimus and tacrolimus in preventing kidney transplantation rejection. Methods: Search was conducted for finding randomized clinical trials (RCT) until the end of 2013 in main databases include Cochrane, Medline and other related databases in February 2014. To find the ongoing trials two databases were searched (Clinicaltrial. gov and irct.ir/fa/). Two independent reviewers checked studies for quality and eligibility and finally extracted the data. Data extraction was performed using Cochrane data extraction form for clinical trial. Discrepancies were resolved via consultation with third person. The studies examined in term of heterogeneity with I2 and Chi-square test. The mata-analysis was carried out using RevMan 5.2 (Wintertree Software Inc, Ontario, Canada) when there was homogeneity. Results: Finally, seven reports from six RCTs included in this study. All reports were in english language and total numbers of participant in these studies were 824. No studies were found in comparison of everolimus and sirolimus and all seven reports were combination of everolimus, tacrolimus and other relative drugs. Follow up time of studies were different from 6 to 36 months. Due to the heterogeneity of included studies, only two studies were entered into meta-analysis. The recorded mean values for glomerular filtration rate, serum creatinine and creatinine clearance were between 60-80 ml/min, 50 to 80 ml/min and 1.2 to 1.9 mg/dl respectively. The results of meta-analysis in three outcomes include; serum creatinine, creatinine clearance and glomerular filtration rate were significantly in favor of low dose tacrolimus plus everolimus. Conclusion: In general, everolimus showed better results in combination with tacrolimus. Given the available evidence in this study, everolimus in combination with low dose tacrolimus showed better safety and effectiveness in preventing kidney transplantation rejection. [ABSTRACT FROM AUTHOR]