The purpose of this study was to assess the impact of patient population characteristics on accuracy by computed tomography angiography (CTA) to detect obstructive coronary artery disease (CAD). The ability of CTA to exclude obstructive CAD in patients of different pre-test probabilities and in presence of coronary calcification remains uncertain. For the CORE-64 (Coronary Artery Evaluation Using 64-Row Multidetector Computed Tomography Angiography) study, 371 patients underwent CTA and cardiac catheterization for the detection of obstructive CAD, defined as ≥50% luminal stenosis by quantitative coronary angiography (QCA). This analysis includes 80 initially excluded patients with a calcium score ≥600. Area under the receiver-operating characteristic curve (AUC) was used to evaluate CTA diagnostic accuracy compared to QCA in patients according to calcium score and pre-test probability of CAD. Analysis of patient-based quantitative CTA accuracy revealed an AUC of 0.93 (95% confidence interval CI: 0.90 to 0.95). The AUC remained 0.93 (95% CI: 0.90 to 0.96) after excluding patients with known CAD but decreased to 0.81 (95% CI: 0.71 to 0.89) in patients with calcium score ≥600 (p = 0.077). While AUCs were similar (0.93, 0.92, and 0.93, respectively) for patients with intermediate, high pre-test probability for CAD, and known CAD, negative predictive values were different: 0.90, 0.83, and 0.50, respectively. Negative predictive values decreased from 0.93 to 0.75 for patients with calcium score <100 or ≥100, respectively (p = 0.053). Both pre-test probability for CAD and coronary calcium scoring should be considered before using CTA for excluding obstructive CAD. For that purpose, CTA is less effective in patients with calcium score ≥600 and in patients with a high pre-test probability for obstructive CAD.