The History Electrocardiogram Age Risk factor Troponin (HEART) Pathway and Emergency Department Assessment of Chest pain Score (EDACS) are validated accelerated diagnostic pathways designed to risk stratify patients presenting to the emergency department with chest pain. Data from large multisite prospective studies comparing these accelerated diagnostic pathways are limited.The HEART Pathway Implementation is a prospective three-site cohort study, which accrued adults with symptoms concerning for acute coronary syndrome. Physicians completed electronic health record HEART Pathway and EDACS risk assessments on participants. Major adverse cardiac events (death, myocardial infarction and coronary revascularisation) at 30 days were determined using electronic health record, insurance claims and death index data. Test characteristics for detection of major adverse cardiac events were calculated for both accelerated diagnostic pathways and McNemar's tests were used for comparisons.5799 patients presenting to the emergency department were accrued, of which HEART Pathway and EDACS assessments were completed on 4399. Major adverse cardiac events at 30 days occurred in 449/4399 (10.2%). The HEART Pathway identified 38.4% (95% CI 37.0% to 39.9%) of patients as low-risk compared with 58.1% (95% CI 56.6% to 59.6%) identified as low-risk by EDACS (p<0.001). Major adverse cardiac events occurred in 0.4% (95% CI 0.2% to 0.9%) of patients classified as low-risk by the HEART Pathway compared with 1.0% (95% CI 0.7% to 1.5%) of patients identified as low-risk by EDACS (p<0.001). Thus, the HEART Pathway had a negative predictive value of 99.6% (95% CI 99.1% to 99.8%) for major adverse cardiac events compared with a negative predictive value of 99.0% (95% CI 98.5% to 99.3%) for EDACS.EDACS identifies a larger proportion of patients as low-risk than the HEART Pathway, but has a higher missed major adverse cardiac events rate at 30 days. Physicians will need to consider their risk tolerance when deciding whether to adopt the HEART Pathway or EDACS accelerated diagnostic pathway.NCT02056964.