The objective was to compare the image quality, diagnostic accuracy, radiation exposure, and contrast volume of "triple rule-out" (TRO) computed tomography (CT) to other diagnostic modalities commonly used to evaluate patients with nontraumatic chest pain (dedicated coronary, pulmonary embolism [PE], and aortic dissection CT; invasive coronary angiography; and nuclear stress testing). Four electronic databases were searched, along with reference lists and contacted content experts, for relevant studies from inception until October 2012. Eligible studies enrolled patients with nontraumatic chest pain, shortness of breath, suspected acute coronary syndrome (ACS), PE, or aortic dissection; used at least 64-slice CT technology; and compared TRO CT to another diagnostic modality. Eleven studies enrolling 3,539 patients (791 TRO and 2,748 non-TRO) were included (one randomized controlled trial and 10 observational). There was no significant difference in image quality between TRO and dedicated CT scans. TRO CT had the following pooled diagnostic accuracy estimates for coronary artery disease: sensitivity of 94.3% (95% confidence interval [CI] = 89.1% to 97.5%), specificity of 97.4% (95% CI = 96.1% to 98.4%), positive likelihood ratio (LR+) of 17.71 (95% CI = 3.92 to 79.96), and negative likelihood ratio (LR-) of 0.08 (95% CI = 0.02 to 0.27). There were insufficient numbers of patients with PE or aortic dissection to generate diagnostic accuracy estimates for these conditions. Use of TRO CT involved greater radiation exposure (mean difference [MD] = 4.84 mSv, 95% CI = 1.65 to 8.04 mSv) and contrast exposure (MD = 38.0 mL, 95% CI = 28.1 to 48.0 mL) compared to non-TRO CT patients. Triple rule-out CT is highly accurate for detecting coronary artery disease. Given the low (<1%) prevalence of PE and aortic dissection in the included studies, and the increased radiation and contrast exposure, there are insufficient data to recommend use of TRO CT in the diagnosis of these conditions.