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Background: We desired to determine cardiac troponin (cTn) concentrations necessary to achieve a positive predictive value (PPV) of ≥75% for acute myocardial infarction (AMI) to justify immediate admission of patients to a monitored unit and, in general, early coronary angiography., Methods: In a prospective multicenter diagnostic study enrolling patients presenting to the emergency department with symptoms suggestive of AMI, final diagnoses were adjudicated by 2 independent cardiologists based on clinical information including cardiac imaging. cTn concentrations were measured using 5 different sensitive and high-sensitivity cTn (hs-cTn) assays in a blinded fashion at presentation and serially thereafter. The diagnostic end point was PPV for rule-in of AMI of initial cTn concentrations alone and in combination with early changes., Results: Among 3828 patients, 616 (16%) had an AMI. At presentation, 7% to 14% of patients had cTnT/I concentrations associated with a PPV of ≥75%. Adding absolute or relative changes did not significantly further increase the PPV. PPVs increased from 46.5% (95% CI, 43.6-49.4) for hs-cTnT at presentation >14 ng/L to 78.9% (95% CI, 74.7-82.5) for >52 ng/L ( P < 0.001), whereas PPVs in higher hs-cTnT strata remained largely unchanged [e.g., 82.4% (95% CI, 77.5-86.7) for >80 ng/L vs 83.9% (95% CI, 76.0-90.1) for >200 ng/L ( P = 0.72)]. The addition of early changes in hs-cTnT further increased the PPV up to 60 ng/L, but not for higher concentrations., Conclusions: Serial sampling does not seem necessary for predicting AMI and concurrent decision-making in about 10% of patients, as it only marginally increases the PPV for AMI and not in a statistically or clinically significant way., Clinicaltrialsgov Identifier: NCT00470587., (© 2018 American Association for Clinical Chemistry.)