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Background— Vascular closure devices (VCDs) are effective in reducing the time to ambulation for patients undergoing cardiac catheterization procedures and in reducing the risk of vascular complications in selected patient cohorts. However, the frequency and consequence of failure of VCDs is not well defined. Methods and Results— From a prospective registry of consecutive patients undergoing cardiac catheterization at our center, 9823 patients who received either a collagen plug-based (Angio-Seal) or a suture-based (Perclose) VCD were selected for the study. VCD failure was defined as unsuccessful deployment or failure to achieve hemostasis. Major vascular complication was defined as any retroperitoneal hemorrhage, limb ischemia, or any surgical repair. Minor vascular complication was defined as any groin bleeding, hematoma (≥5 cm), pseudoaneurysm, or arteriovenous fistula. Any vascular complication was defined as either a major or minor vascular complication. Among the 9823 patients in the study, VCD failed in 268 patients (2.7%; 2.3% diagnostic versus 3.0% percutaneous coronary intervention; P =0.029). Patients with VCD failure had significantly increased risk of any (6.7% versus 1.4%; P <0.0001), major (1.9% versus 0.6%; P =0.006), or minor (6.0% versus 1.1%; P <0.0001) vascular complication compared with the group with successful deployment of VCD. The increased risk of vascular complication was unchanged in a propensity score-matched cohort. Conclusions— In contemporary practice, VCD failure is rare, but when it does fail, it is associated with a significant increase in the risk of vascular complications. Patients with VCD failure should be closely monitored.