BACKGROUND Chest pain and its clinical manifestations are the most common reasons for presentation to the emergency department (ED). Given that the prevalence of chest pain due to acute myocardial infarction (AMI) in the ED is modest, clinicians should use cardiac troponins to safely and rapidly rule out AMI, avoiding the delayed release of low risk patients. The study aims to develop and validate an algorithm to early rule-out of non-ST elevation myocardial infarction (NSTEMI) in subjects admitted to the ED with symptoms of myocardial infarction. METHODS High sensitivity cardiac Troponin T (hs-cTnT) serial measurements (baseline, T0; after 1 h, T1; after 3 h, T3) were used to develop and validate the algorithm, respectively, in 6403 and 773 consecutive admissions suggestive of AMI. RESULTS Patients were classified as having or not having NSTEMI according to clinical assessment, diagnostic imaging, and serial measurements ofhs-cTnT; ROC curve analysis allowed to find changes in consecutive hs-cTnT associated with diagnostic sensitivity close to 100%. Only patients with hs-cTnTat T0 lower than 14 ng/L resultedto be eligible for the safe rule-out of NSTEMI. CONCLUSIONS Although some points remain to be improved, the results obtained indicate that algorithms for fast NSTEMI rule-out are feasible and safe.