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Summary: Cytomegalovirus (CMV) infection is common in kidney transplantation (KT). Antiviral‐agents are used as universal prophylaxis. Our purpose aimed to compare and rank efficacy and safety. MEDLINE, Embase, SCOPUS, and CENTRAL were used from inception to September 2020 regardless language restriction. We included randomized clinical trials (RCTs) comparing the CMV infection/disease prophylaxis among antiviral‐agents in adult KT recipients. Of 24 eligible RCTs, prophylactic valganciclovir (VGC) could significantly lower the overall CMV infection and disease risks than placebo with pooled risk differences (RDs) [95% confidence interval (CI)] of −0.36 (−0.54, −0.18) and −0.28 (−0.48, −0.08), respectively. Valacyclovir (VAC) and ganciclovir (GC) significantly decreased risks with the corresponding RDs of −0.25 (−0.32, −0.19) and −0.30 (−0.37, −0.22) for CMV infection and −0.26 (−0.40, −0.12) and −0.22 (−0.31, −0.12) for CMV disease. For subgroup analysis by seropositive‐donor and seronegative‐recipient (D+/R−), VGC and GC significantly lowered the risk of CMV infection/disease with RDs of −0.42 (−0.84, −0.01) and −0.35 (−0.60, −0.12). For pre‐emptive strategies, GC lowered the incidence of CMV disease significantly with pooled RDs of −0.33 (−0.47, −0.19). VGC may be the best in prophylaxis of CMV infection/disease follow by GC. VAC might be an alternative where VGC and GC are not available. [ABSTRACT FROM AUTHOR]