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Supplemental Digital Content is available in the text., Background: High-sensitivity cardiac troponin assays can help to identify patients who are at low risk of myocardial infarction in the emergency department. We aimed to determine whether the addition of clinical risk scores would improve the safety of early rule-out pathways for myocardial infarction. Methods: In 1935 patients with suspected acute coronary syndrome, we evaluated the safety and efficacy of 2 rule-out pathways alone or in conjunction with low-risk TIMI (Thrombolysis In Myocardial Infarction) (0 or 1), GRACE (Global Registry of Acute Coronary Events) (≤108), EDACS (Emergency Department Assessment of Chest Pain Score) (99th percentile) myocardial infarction. Results: Myocardial infarction or cardiac death during the index presentation or at 30 days occurred in 14.3% of patients (276/1935). The European Society of Cardiology pathway ruled out 70%, with 27 missed events giving a negative predictive value of 97.9% (95% CI, 97.1–98.6). The addition of a HEART score ≤3 reduced the proportion ruled out by the European Society of Cardiology pathway to 25% but improved the negative predictive value to 99.7% (95% CI, 99.0–100; P