To assess the long-term outcome and hospital readmission rate associated with a computed tomographic (CT) angiography-guided strategy used to examine patients who present to the emergency department (ED) with symptoms of possible acute coronary syndrome (ACS). The study was approved by the institutional review board, and all patients provided written informed consent. A total of 585 consecutive patients (mean age, 58 years ± 11 [standard deviation]; 58% were male) with ischemic-type chest pain and low to intermediate risk for ACS were evaluated prospectively. Patients underwent coronary CT angiography after single or serial troponin I (TnI) measurement, depending on time of presentation to the ED. Subsequent care was determined with CT angiography findings: Patients without plaque and patients with nonobstructive plaque and at most mild to moderate stenosis (<40% luminal narrowing) were discharged without further investigation. Patients with moderate stenosis (40%-70% narrowing) were discharged and referred for outpatient stress echocardiography. Patients with severe stenosis (>70% narrowing) were admitted. Discharged patients were contacted and their medical records were reviewed to determine rates of death, ACS, revascularization, and hospital admission. By using binomial distribution, Clopper-Pearson confidence intervals (CIs) were calculated for outcome data. Coronary CT angiography findings were as follows: A total of 196 patients (34%) had no coronary plaque or stenosis, 288 (49%) had nonobstructive plaque, 22 (4%) had moderate stenosis, and 79 (13%) had severe stenosis. At median 47.4-month follow-up (range, 24-57 months) of the 506 discharged patients, five (1%; 95% CI: 0.4%, 2.3%) had been readmitted for chest pain; there were no instances of coronary revascularization, ACS, or death (0% for all; 95% CI: 0%, 0.7%). Follow-up was 100% complete. Use of a CT angiography-guided strategy to investigate patients with low to intermediate risk of ACS who present to the ED with chest pain is safe at long-term follow-up, including patients discharged after single TnI measurement.