The data about the accuracy of dual-axis rotational coronary angiography (DARCA) in detecting coronary artery disease (CAD) is scare. This study aimed to compare the diagnostic accuracy of DARCA versus standard coronary angiography (SA). 70 patients with possible CAD underwent SA following by DARCA were prospectively enrolled. The primary endpoint was the non-inferiority comparison of the two modalities regarding diagnosis of CAD. Coronary lesion assessment, quantitative coronary angiography (QCA) analysis, and screening adequacy comparisons were performed. All images were analyzed by two independent reviewers except QCA analysis that was analyzed by the third independent reviewer. Radiation dose, contrast usage and procedural time were recorded. This trial is registered with ClinicalTrials.gov, Number NCT01776866. 63 of 70 patients were analyzed. DARCA was non-inferior to SA regarding the diagnosis of CAD (reviewer one—positive agreement: 100%, negative agreement: 100%, p = 1; p = 0.003 for non-inferiority; reviewer two—positive agreement: 96%, negative agreement: 95%, p = 1; p = 0.016 for non-inferiority). All reviewers showed good agreement between the two modalities for the diagnosis of CAD, coronary lesion assessment, QCA analysis, and screening adequacy, as reflected by kappa coefficients between 0.61 and 1.00. DARCA was associated with 41% reduction in radiation dose, 30% in contrast usage and 29% in procedure time (all p < 0.001). DARCA is clinically comparable to SA concerning the diagnostic accuracy for CAD, while markedly reduces radiation dose, contrast usage and procedure time.