Introduction: Rapid diagnostic algorithms using high-sensitivity cardiac troponin can rapidly diagnose or exclude acute myocardial infarction (MI). However, multiple algorithms have been proposed and it is unclear if some outperform others. The objective of this study was to prospectively compare the diagnostic performance of 1- and 2-hour algorithms in clinical practice in a Canadian population. Methods: Emergency department patients with chest pain had high-sensitivity cardiac troponin-T (hs-cTnT) collected on presentation and 1- and 2-hours later at a single academic tertiary hospital and regional percutaneous coronary intervention site over a 2-year period. The primary outcome was index MI, the secondary outcome was 30-day major adverse cardiac events (MACE). All outcomes were 2 physician adjudicated. Results: We enrolled 1,167 patients with hs-cTnT collected on ED presentation. Of these, 350 had a valid 1-hour and 550 had a 2-hour hs-cTnT sample. Index MI prevalence was ~11%. Sensitivity of the 1- and 2-hour algorithms for index MI was 97.3% (95% CI 85.8-99.9%) and 100% (95% CI 91.6-100%) and for 30-day MACE was 80.9% (95% CI 66.7-90.9%) and 83.3% (95% CI 73.2-90.8%), respectively. The 1-hour algorithm was 96.3% specific for index MI (95% CI 93.8-98.2%) whereas specificity for the 2-hour algorithm was 97.9% (95% CI 96.3-100%). Both algorithms classified about one-quarter of patients in an indeterminate observational zone with an ~11% MI prevalence. Conclusion: Both the 1- and 2-hour algorithms were highly sensitive and specific for MI, but were less sensitive for 30-day MACE. However, the 2-hour algorithm trended toward better performance, likely because its larger delta cutoffs reduce the risk of misclassification owing to analytic variability. These findings suggest algorithms using larger delta cutoffs may provide a greater margin of safety. Further comparative evaluation of rapid diagnostic algorithms using different cutoffs and characterization of patients in the observational zone is warranted.