To compare outcomes of single (intervention group: del Nido [DN], and histamine-tryptophan-ketoglutarate) versus multidose (control group) cardioplegia in the adult cardiac surgery patients. Medical search engines were interrogated to identify relevant randomized controlled trials and propensity-score matched cohorts. Meta-analysis was conducted for primary (in-hospital/30-day mortality) and secondary (ischemic and cardiopulmonary bypass [CPB] times, reperfusion fibrillation, peak of cardiac enzymes, myocardial infarction) endpoints. Subgroup analyses were conducted for study design and type of intervention, and meta-regression for primary outcome included type of surgery and left ventricular ejection fraction as moderators. Ten randomized controlled trials and 13 propensity-score matched cohorts were included, reporting on 5516 patients. Estimates are expressed as (parameter value [OR, odds ratio; MD, mean difference; SMD, standardized mean difference]/unit of measure [95% confidence interval], P value). DN reduced ischemic time (MD, -7.18 minutes [-12.52 to -1.84], P < .01), CPB time (MD, -10.44 minutes [-18.99 to -1.88], P .01), reperfusion fibrillation (OR, 0.16 [0.05-0.54], P < .01), and cardiac enzymes (SMD -0.17 [-0.29, 0.05], P < .01) compared with multidose cardioplegia. None of these beneficial effects were reproduced by histamine-tryptophan-ketoglutarate, which instead increased CPB time (MD, 2.04 minutes [0.73-3.37], P < .01) and reperfusion fibrillation (OR, 1.80 [1.20-2.70], P < .01). There was no difference in mortality and myocardial infarction between single and multidose, independently of type of surgery or left ventricular ejection fraction. DN decreases operative times, reperfusion fibrillation, and surge of cardiac enzymes compared with multidose cardioplegia. Copyright © 2019 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.