AIM: To assess the advantages and disadvantages of immunosuppression monotherapy after transplantation and the impact of monotherapy on hepatitis C virus (HCV) recurrence. METHODS: Articles from Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded, including non-English literature identified in these databases, were searched up to January 2013. We included randomized clinical trials comparing various immunosuppression monotherapy and prednisone-based immunosuppression combinations for liver transplantation. The modified Jadad scale score or the Oxford quality scoring system was used. Meta-analyses were performed with weighted random-effects models. RESULTS: A total of 14 randomized articles including 1814 patients were identified. Eight trials including 1214 patients compared tacrolimus monotherapy (n = 610) vs tacrolimus plus steroids or triple therapy regarding acute rejection and adverse events (n = 604). Five trials, including 285 patients, compared tacrolimus monotherapy (n = 143) vs tacrolimus plus steroids or triple therapy regarding hepatitis C recurrence (n = 142). Four trials including 273 patients compared cyclosporine monotherapy (n = 148) vs cyclosporine and steroids regarding acute rejection and adverse events (n = 125). Two trials including 170 patients compared mycophenolate mofetil monotherapy (n = 86) vs combinations regarding acute rejection (n = 84). There were no significant differences in the acute rejection rates between tacrolimus monotherapy (RR = 1.04, P = 0.620), and cyclosporine monotherapy (RR = 0.89, P = 0.770). Mycophenolate mofetil monotherapy had a significant increase in the acute rejection rate (RR = 4.50, P = 0.027). Tacrolimus monotherapy had no significant effects on the recurrence of hepatitis C (RR = 1.03, P = 0.752). More cytomegalovirus infection (RR = 0.48, P = 0.000) and drug-related diabetes mellitus (RR = 0.54, P = 0.000) were observed in the immunosuppression combination therapy groups. CONCLUSION: Tacrolimus and cyclosporine monotherapy may be as effective as immunosuppression combination therapy. Mycophenolate mofetil monotherapy was not considerable. Tacrolimus monotherapy does not increase recurrence of HCV. (C) 2014 Baishideng Publishing Group Inc. All rights reserved.