We compared a rapid, point-of-care multimarker protocol with a single and serial troponin I (TnI)-only protocol in 5,244 patients admitted to the emergency department with chest pain. The diagnosis of acute myocardial infarction (AMI) was based on a doubling myoglobin level accompanied by at least a 50% increase in the creatine kinase (CK)-MB level with no detectable TnI; a doubling of myoglobin level together with any detectable TnI; or a TnI level of 0.4 ng/mL (0.4 microg/L) or more, irrespective of myoglobin or CK-MB results. By using these new criteria, 145 of 148 cases were positive for AMI (positive predictive value [PPV], 92.4%) and 3 were negative, which were also negative by the core laboratory TnI assay. Twelve confirmed non-AMI cases were positive by the new protocol, with 10 of 12 confirmed by the core laboratory as positive for TnI. The negative predictive value (NPV) was 99.9% the overall diagnostic accuracy was 99.7%. The TnI-only protocol had a sensitivity of 68.2% with an NPV of 99.1%. With lower TnI-only cutoffs, 4 patients had false-negative results, and a PPV of 36.4% was observed. Our rapid multimarker protocol seems superior to a TnI-only approach for rapidly triaging patients with chest pain or AMI.