We compared the use of manual compression and Angio-Seal and Starclose arterial closure devices to achieve hemostasis following common femoral artery (CFA) punctures in order to evaluate safety and efficacy. A prospective nonrandomized, single-center study was carried out on all patients undergoing CFA punctures over 1 year. Hemostasis was achieved using manual compression in 108 cases, Angio-Seal in 167 cases, and Starclose in 151 cases. Device-failure rates were low and not significantly different in the two groups (manual compression and closure devices; p = 0.8). There were significantly more Starclose (11.9%) patients compared to Angio-Seal (2.4%), with successful initial deployment subsequently requiring additional manual compression to achieve hemostasis (p < 0.0001). A significant number of very thin patients failed to achieve hemostasis (p = 0.014). Major complications were seen in 2.9% of Angio-Seal, 1.9% of Starclose, and 3.7% of manual compression patients, with no significant difference demonstrated; 4.7% of the major complications were seen in female patients compared to 1.3% in males (p = 0.0415). All three methods showed comparable safety and efficacy. Very thin patients are more likely to have failed hemostasis with the Starclose device, although this did not translate into an increased complication rate. There is a significant increased risk of major puncture-site complications in women with peripheral vascular disease.