Background: We aimed to evaluate the efficacy and safety of using high-sensitivity cardiac troponin T (hs-cTnT) within an accelerated diagnostic protocol (ADP) in patients presenting with symptoms suggestive of acute myocardial infarction (AMI) for rapid rule-out of AMI. Methods: In two independent large multicenter studies, levels of hs-cTnT at presentation and at 2 h were combined with the Throm bolysis In Myocardial Infarction (TIMI) risk score and ECG findings. The ADP defined patients with normal levels of hs-cTnT at presentation and 2 h, a TIMI score =1, and normal ECG findings as candidates for rapid rule-out of AMI and rapid discharge. Major adverse cardiac events (MACEs) occurring within 30-days were centrally adjudicated by two independent cardiologists. Results: In the derivation cohort, among 1085 consecutive patients 198 patients (18.2 ) had a MACE. The ADP classified 374 patients (34.5 ) as low-risk. None of these patients had a MACE at 30 days, resulting in a negative predictive value (NPV) of 100 (95 CI, 99.0-100 ) and a sensitivity of 100 (95 CI, 98.2 -100 ). In the validation cohort, among 1590 consecutive patients 231 patients (14.5 ) had a MACE. The ADP classified 641 patients (40.3 ) as low-risk. 6 of these patients had a MACE at 30 days, resulting in a NPV of 99.1 (95 CI, 98.0-99.6 ) and a sensitivity of 97.4 (95 CI, 94.5-98.8 ). Conclusions: The ADP including hs-cTnT allows early identification 35 to 40 of patients to be at extremely low risk of MACE and therefore ideal candidates for outpatient management.