BACKGROUND: "Triple rule-out" CT angiography simultaneously evaluates coronary artery disease, pulmonary embolism, and aortic dissection in a single imaging examination. However, the clinical outcomes of this approach are unknown. OBJECTIVE: Using standard cardiac CT angiography as a reference, this study was performed to describe the diagnostic yield and clinical outcomes of patients undergoing triple rule-out in clinical practice. METHODS: We identified consecutive patients at 2 institutions undergoing triple rule-out or cardiac CT angiography for acute chest pain. The primary outcome was a composite diagnostic yield consisting of coronary artery diameter stenosis >50%, pulmonary embolism, and aortic dissection. Other reported outcomes included radiation dose, downstream resource use, and 90-day clinical outcomes. RESULTS: Among 2068 patients (272 triple rule-out and 1796 cardiac CT angiograms), the composite diagnostic yield was 14.3% with triple rule-out and 16.3% with cardiac CT (P = 0.41) and was driven by the diagnosis of obstructive coronary artery disease (13.2% triple rule-out versus 16.1% cardiac CT, P = 0.22). The diagnostic yield for pulmonary embolism was low (1.1% triple rule-out and 0.2% cardiac CT, P = 0.052) and no aortic dissections were found in either group. Compared with cardiac CT, the triple rule-out approach was associated with higher radiation exposure (12.0 +/- 5.6 mSv versus 8.2 +/- 4.0 mSv, P < 0.0001), a greater incidence of subsequent emergency center cardiac evaluations (5.9% versus 2.5%, P = 0.0017), and more downstream pulmonary embolism-protocol CT angiography (3.3% versus 0.9%, P = 0.0034). CONCLUSIONS: Among patients with acute chest pain, a triple rule-out approach resulted in higher radiation exposure compared with cardiac CT, but was not associated with improved diagnostic yield, reduced clinical events, or diminished downstream resource use. (C) 2011 Society of Cardiovascular Computed Tomography. All rights reserved.