Vascular closure devices (VCDs) were introduced in the early 1990s with the goal of limiting the time, labor, bed rest, and patient discomfort associated with manual compression (MC) for hemostasis after cardiovascular interventions. However, its advantage over MC has not been extensively studied after interventional procedures. The aim of this study was to do prospective, randomized study comparing the safety and efficacy of the Angio-Seal (AS) to that of MC in patients undergoing transfemoral coronary and peripheral vascular interventional procedure. A prospective, randomized trial was undertaken on consecutive series of patients admitted to King Fahd Hospital of the University for transfemoral coronary and peripheral vascular interventional procedures over 1 year. The study was designed to compare the hemostasis time in minutes and the incidence of vascular complications in patients receiving AS with those undergoing MC. All patients were on antiplatelets and received heparin during the procedure. During the study period, 160 patients were included, 80 in each group. There was a significant difference in mean time to hemostasis in minutes (15.83 ± 1.63 minutes for MC and 0.42 ± 0.04 minutes for the AS; p < 0.001), time to ambulation in minutes (280 ± 15 for MC and 120 for AS; p = 0.04) and in minor complications (33.8% in MC vs. AS 5%; p < 0.001). However, the major complication rate did not significantly differ between the two groups (0% in AS vs. 2.5% in MC; p = 0.15). AS was found to achieve rapid closure of the femoral access site safely in patients undergoing coronary and peripheral vascular interventional procedures under antiplatelets and systemic heparinization.