Background Although it is well known that vascular closure devices (VCD) are commonly used in therapeutic interventional radiological procedures, standard use in diagnostic procedures is not as well studied. Purpose The aim of this study was to determine the real-world safety and effectiveness of the VCD in both diagnostic and therapeutic interventional radiological procedures. Materials and methods A retrospective, single center study included all patients where VCDs were used for either a diagnostic or therapeutic interventional procedure. Various demographic and clinical risk factors were recorded and examined for any significant association with successful deployment and complications. Results A total of 2072 patients were included. VCDs were successfully deployed in 95.2% of the patients with 4.8% of perioperative complications, which included minor oozing from the puncture site, small hematoma less than or equal to 5 cm, large hematoma greater than 5 cm, pain, and loss of vascular access. Therapeutic (vascular interventional radiology (VIR) and neuro-interventional radiology (NIR)) procedures (OR 3.03, 95% CI 1.51–6.09, p = 0.002), use of Angioseal (OR 5.26, 95% CI 3.13–8.33), p < 0.001), and no use of antiplatelet medications (OR 0.47, 95% CI 0.22–0.97, p = 0.041) were independently associated with successful deployment of VCDs when controlled for other risk factors. Smoking (OR 3.50, 95% CI 2.00–6.05, p = <0.001), use of antiplatelet (OR 2.01, 95% CI 1.04–3.87, p = 0.037) and use of heparin (OR 1.78, 95% CI 1.10–2.86, p = 0.018) were independently associated with higher complication rates. Conclusion VCD's were successfully deployed in 95.2% of the patients with 4.8% of perioperative minor complications.