Multi-slice computed tomography (MSCT) has proven in several studies to have a high diagnostic accuracy for the detection or exclusion of coronary artery disease. A major concern with coronary MSCT, however, is the associated radiation exposure of patients. Recent studies suggest that use of a 64-slice scanner is associated with a non-negligible lifetime attributable risk of cancer. Several strategies can be used to reduce patient exposure in coronary MSCT. The purpose of this multicenter study was to investigate the effects of the adjustment of tube voltage and current on radiation dose and image interpretability. MSCT with retrospective ECG gating was performed in 315 patients. The dose-length product (DLP) in the patients enrolled with the dose reduction protocol resulted in a 36% overall reduction in the mean radiation dose (911 ± 289 mGy.cm) compared with the standard protocol (1427 ± 226 mGy.cm, p < 0.001). Nevertheless, image interpretability was maintained. This study on coronary MSCT demonstrates that the radiation dose can be significantly reduced by parameter optimization, with maintained image interpretability.