Objectives: This study aimed to test whether advanced cardiovascular injection (ACI) via 4 French (Fr) catheters is more advantageous than manual injection with 6 Fr catheters. Background: For coronary angiography, proponents of contrast media ACI believe it utilizes smaller-diameter catheters when compared with manual injection, without compromising the quality of the angiogram, and has the potential to reduce the amount of contrast used and lessen the use of closure devices. Methods: In a prospective study, 200 consecutive patients referred for elective coronary angiography were randomized to standard 6 Fr catheters with manual injection versus 4 Fr catheters with ACI. The study's primary endpoint is the quality of the coronary angiogram. Secondary endpoints include groin complications, utilization of closure devices, and volume of contrast media. Thirty-six patients who underwent ad hoc percutaneous coronary intervention were excluded from the analysis. Results: The final analysis included 80 patients treated with 4 Fr catheters with ACI and 84 patients treated with 6 Fr catheters with manual injection. The groups had similar demographic and clinical characteristics. The quality of the angiogram was similar between groups with the exception of more left coronary sinus flush with 4 Fr catheters (3.57 ± 1.1 vs. 2.98 ± 0.9, P < 0.001) and less closure device use with 4 Fr (25 vs. 71.4%, P < 0.01) compared to 6 Fr catheters. The procedure duration, volume of contrast used, vascular complications, and time to ambulation were similar between groups (all P > 0.05). Conclusions: 4 Fr diagnostic catheters with ACI offer similar quality coronary angiograms, similar rates of vascular complications, procedure duration, contrast used, and time to ambulation, but have a significantly lesser need for closure devices compared to the 6 Fr system with manual injection. © 2011 Wiley-Liss, Inc.