Approximately 50% of heart transplant programs currently employ a strategy of induction therapy (IT) with either interleukin-2 receptor antagonists (IL2RA) or polyclonal anti-thymocyte antibodies (ATG) during the early postoperative period. However, the overall utility of such therapy is uncertain and data comparing induction protocols are limited. The authors searched PubMed, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.​gov through January 2018 for randomized controlled trials (RCTs) or observational controlled studies of IT vs no IT and IL2RA vs ATG. Inverse variance fixed effects models with odds ratio (OR) as the effect measure were used for primary analyses. Main outcomes include moderate and severe rejection, all-cause mortality, infection, and cancer. The authors’ search retrieved 2449 studies, of which 11 met criteria for inclusion (8 RCTs and 3 observational case-control studies). Quality of evidence for RCTs was moderate to high. Overall, patients receiving IT had similar risk of moderate-to-severe rejection, all-cause death, infection, and cancer with patients who did not receive IT. The use of IL2RA was associated with significantly higher risk of moderate-to-severe rejection than ATG (OR 3.4; 95% CI 1.4 to 8.1), but similar risk of death, infections, and cancer. The use of IT was not associated with any benefits or harms compared with no IT. Moderate-to-severe rejection may be reduced by ATG compared with IL2RA.