Objectives: To compare the diagnostic performance and radiation exposure of 128-slice dual-source CT coronary angiography (CTCA) protocols to detect coronary stenosis with more than 50 % lumen obstruction. Methods: We prospectively included 459 symptomatic patients referred for CTCA. Patients were randomized between high-pitch spiral vs. narrow-window sequential CTCA protocols (heart rate below 65 bpm, group A), or between wide-window sequential vs. retrospective spiral protocols (heart rate above 65 bpm, group B). Diagnostic performance of CTCA was compared with quantitative coronary angiography in 267 patients. Results: In group A (231 patients, 146 men, mean heart rate 58 ± 7 bpm), high-pitch spiral CTCA yielded a lower per-segment sensitivity compared to sequential CTCA (89 % vs. 97 %, P = 0.01). Specificity, PPV and NPV were comparable (95 %, 62 %, 99 % vs. 96 %, 73 %, 100 %, P > 0.05) but radiation dose was lower (1.16 ± 0.60 vs. 3.82 ± 1.65 mSv, P < 0.001). In group B (228 patients, 132 men, mean heart rate 75 ± 11 bpm), per-segment sensitivity, specificity, PPV and NPV were comparable (94 %, 95 %, 67 %, 99 % vs. 92 %, 95 %, 66 %, 99 %, P > 0.05). Radiation dose of sequential CTCA was lower compared to retrospective CTCA (6.12 ± 2.58 vs. 8.13 ± 4.52 mSv, P < 0.001). Diagnostic performance was comparable in both groups. Conclusion: Sequential CTCA should be used in patients with regular heart rates using 128-slice dual-source CT, providing optimal diagnostic accuracy with as low as reasonably achievable (ALARA) radiation dose. Key Points: • 128-slice dual-source CT coronary angiography offers several different acquisition protocols. • Randomized comparison of protocols reveals an optimal protocol selection strategy. • Appropriate CTCA protocol selection lowers radiation dose, while maintaining high quality. • CTCA protocol selection should be based on individual patient characteristics. • A prospective sequential protocol is preferred for CTCA.