Study objective: The objectives of this systematic review and meta-analysis are to appraise the evidence in regard to the diagnostic accuracy of a low-risk History, ECG, Age, Risk Factors, and Troponin (HEART) score for prediction of major adverse cardiac events in emergency department (ED) patients. These included 4 subgroup analyses: by geographic region, the use of a modified low-risk HEART score (traditional HEART score [0 to 3] in addition to negative troponin results), using conventional versus high-sensitivity troponin assays in the HEART score, and a comparison of different post–ED-discharge patient follow-up intervals. Methods: We searched MEDLINE, EBSCO, Web of Science, and Cochrane Database for studies on the diagnostic performance of low-risk HEART scores to predict major adverse cardiac events among ED chest pain patients. Two reviewers independently screened articles for inclusion, assessed the quality of studies with both an adapted Quality Assessment of Diagnostic Accuracy Studies version 2 tool and an internally developed tool that combined components of the Quality in Prognostic Studies; Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies; and Grading of Recommendations Assessment, Development and Evaluation. Pooled sensitivity, specificity, positive predictive value, negative predictive value, and positive and negative likelihood ratios were calculated. Results: There were 25 studies published from 2010 to 2017, with a total of 25,266 patients included in the final meta-analysis, of whom 9,919 (39.3%) were deemed to have low-risk HEART scores (0 to 3). Among patients with low-risk HEART scores, short-term major adverse cardiac events (30 days to 6 weeks) occurred in 2.1% of the population (182/8,832) compared with 21.9% of patients (3,290/15,038) with non–low-risk HEART scores (4 to 10). For patients with HEART scores of 0 to 3, the pooled sensitivity of short-term major adverse cardiac event predictions was 0.96 (95% confidence interval [CI] 0.93 to 0.98), specificity was 0.42 (95% CI 0.36 to 0.49), positive predictive value was 0.19 (95% CI 0.14 to 0.24), negative predictive value was 0.99 (95% CI 0.98 to 0.99), positive likelihood ratio was 1.66 (95% CI 1.50 to 1.85), and negative likelihood ratio was 0.09 (95% CI 0.06 to 0.15). Subgroup analysis showed that lower short-term major adverse cardiac events occurred among North American patients (0.7%), occurred when modified low-risk HEART score was used (0.8%), or occurred when high-sensitivity troponin was used for low-risk HEART score calculations (0.8%). Conclusion: In this meta-analysis, despite its use in different patient populations, the troponin type used, and timeline of follow-up, a low-risk HEART score had high sensitivity, negative predictive value, and negative likelihood ratio for predicting short-term major adverse cardiac events, although risk of bias and statistical heterogeneity were high.