Background: The role of vascular closure devices (VCDs) in patients having percutaneous coronary intervention (PCI) is controversial, and recommendations for use vary. Objective: To examine the use of and outcomes associated with VCDs in real-world practice. Design: Observational cohort study. Setting: 32 hospitals in Michigan that participate in a large multicenter quality improvement collaborative. Patients: Consecutive patients having emergent and nonemergent PCI from 2007 to 2009. Measurements: Vascular complications and the need for transfusion. Results: Of the 85 048 PCIs performed during the study that met the inclusion criteria, 28 528 (37%) procedures used VCDs. In propensity score-matched analysis, VCDs were associated with reductions in vascular complications (odds ratio [OR], 0.78 [95% CI, 0.67 to 0.90]; P = 0.001) and postprocedure transfusions (OR, 0.85 [CI, 0.74 to 0.96]; P = 0.011). These findings were consistent across many prespecified subgroups except for patients with a body mass index (BMI) less than 25 kg/m2 and those treated with platelet glycoprotein (GP) 2b/3a inhibitors, in whom the benefit of VCDs over manual closure was attenuated. When the specific subtypes of vascular complications were evaluated, VCDs were associated with fewer hematomas (OR, 0.69 [CI, 0.58 to 0.83]; P < 0.001) or pseudoaneurysms (OR, 0.54 [CI, 0.38 to 0.76]; P < 0.001) but an increase in the odds of retroperitoneal bleeding (OR, 1.57 [CI, 1.12 to 2.20]; P = 0.009). Limitation: Unmeasured confounding cannot be excluded despite the study having measured and balanced many confounders. Conclusion: Vascular closure devices were associated with a significant reduction in vascular complications and need for transfusion in this large cohort of patients having transfemoral PCI. This benefit was lost in patients receiving GP 2b/3a inhibitors and those with normal or lean BMI and was counterbalanced by a small increase in the more serious risk for retroperitoneal bleeding. Primary Funding Source: Blue Cross Blue Shield of Michigan and the National Science Foundation. © 2013 American College of Physicians.