BACKGROUND: Penetrating keratoplasty is a corneal transplantation procedure in which a full-thickness cornea from the host is replaced by a graft from a donor. The use of various immunosuppressants to prevent graft rejection, the most common cause of graft failure in the late postoperative period, is increasing. OBJECTIVES: To assess the effectiveness of immunosuppressants in the prophylaxis of corneal allograft rejection after high- and normal-risk keratoplasty. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2015, Issue 4), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to May 2015), EMBASE (January 1980 to May 2015), China National Knowledge Infrastructure (CNKI) (January 1913 to February 2015), VIP database (January 1989 to February 2015), Wanfang Data (www.wanfangdata.com) (January 1990 to February 2015), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the English language databases on 18 May 2015 and the Chinese language databases on 20 February 2015. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) assessing the use of immunosuppressants in the prevention of graft rejection, irrespective of publication language. DATA COLLECTION AND ANALYSIS: We used standard procedures expected by Cochrane. The primary outcome was clear graft survival at 12 months after penetrating keratoplasty. Secondary outcomes included graft rejection, best-corrected visual acuity, and quality of life. We defined 'high-risk keratoplasty' as repeat keratoplasty and other indications of reduced graft survival. MAIN RESULTS: We included six studies conducted in Germany (three studies), Iran, India, and China. Three studies were conducted in people undergoing high-risk keratoplasty and investigated three different comparisons: systemic mycophenolate mofetil (MMF) versus no MMF; systemic MMF versus systemic cyclosporine A (CsA); and topical CsA versus placebo. One study compared topical tacrolimus to topical steroid in people with normal-risk keratoplasty, and two studies compared topical CsA to placebo in people experiencing graft rejection after normal-risk keratoplasty. Overall, we considered the trials to be at unclear or high risk of bias.MMF may not improve clear graft survival (risk ratio (RR) 1.06, 95% confidence interval (CI) 0.84 to 1.33, 1 RCT, 87 participants, low-quality evidence) but may reduce the risk of graft rejection (RR 0.49, 95% CI 0.22 to 1.08, 1 RCT, 87 participants, low-quality evidence) compared to no MMF. Visual acuity was not reported.In 1 study of 52 people comparing systemic MMF and systemic CsA, there were no graft failures in the first year of follow-up. Data from the longest follow-up (three years) suggest that there may be little difference in the effect of these two treatments on clear graft survival (RR 1.10, 95% CI 0.90 to 1.35, low-quality evidence). There was low-quality evidence of an increased risk of graft rejection with systemic MMF compared to systemic CsA, but with wide CIs compatible with increased risk with systemic CsA (RR 1.48, 95% CI 0.56 to 3.93, low-quality evidence). Visual acuity was not reported.One study of 84 people comparing topical CsA to placebo did not report clear graft survival at 1 year, which suggests that all grafts survived to 1 year. This study suggests that the use of topical CsA probably leads to little or no difference in graft rejection (RR 1.00, 95% CI 0.39 to 2.58, moderate-quality evidence). At one year, the mean difference (MD) between the two groups in visual acuity was 0.07 (95% CI -0.01 to 0.15, moderate-quality evidence).Topical CsA probably does not have an effect on clear graft survival in people experiencing graft rejection after normal-risk keratoplasty compared to placebo (RR 1.03, 95% CI 0.96 to 1.10, 2 RCTs, 283 participants, moderate-quality evidence). There were inconsistent findings on graft rejection, with one study reporting a reduced incidence of graft rejection in the CsA group (RR 0.35, 95% CI 0.14 to 0.87, 230 participants) but the other study reporting a higher average number of episodes of graft rejection in people treated with CsA (MD 1.30, 95% CI 0.39 to 2.21, 43 participants). Overall, we judged this to be low-quality evidence due to risk of bias and inconsistency. There was no evidence for a difference in visual acuity between the 2 groups at final follow-up (approximately 18 months, range 2 to 33 months) (MD 0.04, 95% CI -0.10 to 0.18, 1 RCT, 43 participants, low-quality evidence).In 1 study comparing topical tacrolimus to topical steroid, the graft survived in all of the 12 treated participants and 20 control participants at 6 months. Graft rejection was rare (0 out of 12 versus 2 out of 20) (RR 0.32, 95% CI 0.02 to 6.21, low-quality evidence). Visual acuity was not reported.None of the studies reported on quality of life. We identified an unpublished trial of basiliximab (Simulect) (NCT00409656), probably completed in 2005. AUTHORS' CONCLUSIONS: Current evidence on the effect of immunosuppressants in the prevention of graft failure and rejection after high- and normal-risk keratoplasty is largely low quality because the number of trials was limited, and, in general, the trials were small and at risk of bias. Future trials should be large enough to detect important clinical effects, conducted with a view to minimising the risk of bias, and they should measure outcomes important to patients.